Head and Neck Cancers

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Head and Neck Cancers

Version 1.2018 — February 15, 2018

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Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Panel Members NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

* David G. Pfister, MD † Þ/Chair Robert L. Foote, MD § John A. Ridge, MD, PhD ¶ Memorial Sloan Kettering Cancer Center Mayo Clinic Cancer Center Fox Chase Cancer Center

* Sharon Spencer, MD §/Vice-Chair Jill Gilbert, MD † James Rocco, MD, PhD ¶ University of Alabama at Birmingham Vanderbilt-Ingram Cancer Center The Ohio State University Comprehensive Comprehensive Cancer Center Cancer Center - James Cancer Hospital Maura L. Gillison, MD, PhD † and Solove Research Institute David Adelstein, MD † The University of Texas Case Comprehensive Cancer Center/ MD Anderson Cancer Center Cristina P. Rodriguez, MD † University Hospitals Seidman Cancer Center and Fred Hutchinson Cancer Research Center/ Cleveland Clinic Taussig Cancer Institute Robert I. Haddad, MD † Seattle Cancer Care Alliance Dana-Farber/Brigham and Women’s Cancer Center Douglas Adkins, MD † Jatin P. Shah, MD, PhD ¶ Siteman Cancer Center at Barnes-Jewish Hospital Wesley L. Hicks, Jr., MD ¶ Memorial Sloan Kettering Cancer Center and Washington University School of Medicine Roswell Park Cancer Institute Randal S. Weber, MD ¶ David M. Brizel, MD § Ying J. Hitchcock, MD † § The University of Texas Duke Cancer Institute Huntsman Cancer Institute MD Anderson Cancer Center at the University of Utah Barbara Burtness, MD † Matthew Witek, MD § Yale Cancer Center/Smilow Cancer Hospital Antonio Jimeno, MD, PhD † University of Wisconsin University of Colorado Cancer Center Carbone Cancer Center Paul M. Busse, MD, PhD § Massachusetts General Hospital Cancer Center Debra Leizman, MD Þ Frank Worden, MD † Case Comprehensive Cancer Center/ University of Michigan Jimmy J. Caudell, MD, PhD § University Hospitals Seidman Cancer Center and Comprehensive Cancer Center Moffitt Cancer Center Cleveland Clinic Taussig Cancer Institute Sue S. Yom, MD, PhD § Anthony J. Cmelak, MD § Ellie Maghami, MD ¶ ξ UCSF Helen Diller Family Vanderbilt-Ingram Cancer Center City of Hope Comprehensive Cancer Center Comprehensive Cancer Center A. Dimitrios Colevas, MD † Loren K. Mell, MD § Weining Zhen, MD § Stanford Cancer Institute UC San Diego Moores Cancer Center Fred & Pamela Buffett Cancer Center David W. Eisele, MD ¶ Bharat B. Mittal, MD § The Sidney Kimmel Comprehensive Robert H. Lurie Comprehensive Cancer NCCN Cancer Center at Johns Hopkins Center of Northwestern University Jennifer Burns Susan Darlow, PhD Moon Fenton, MD, PhD † Harlan A. Pinto, MD † Þ The University of Tennessee Stanford Cancer Institute Health Science Center † Medical oncology ¶ Surgery/Surgical oncology Continue § Radiation oncology ξ Otolaryngology Þ Internal medicine NCCN Guidelines Panel Disclosures * Discussion Writing Committee Member

NCCN Guidelines Version 1.2018 Subcommittees NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Principles of Radiation Therapy Principles of Systemic Therapy Principles of Surgery Sharon Spencer, MD §/Lead David G. Pfister, MD † Þ/Lead Randal S. Weber, MD ¶/Lead University of Alabama at Birmingham Memorial Sloan Kettering Cancer Center The University of Texas Comprehensive Cancer Center MD Anderson Cancer Center A. Dimitrios Colevas, MD † David Brizel, MD § Stanford Cancer Institute David M. Brizel, MD § Duke Cancer Institute Duke Cancer Institute Robert I. Haddad, MD † Paul M. Busse, MD, PhD § Dana-Farber/Brigham and Women’s David W. Eisele, MD ¶ Massachusetts General Hospital Cancer Center The Sidney Kimmel Comprehensive Cancer Center Cancer Center at Johns Hopkins Frank Worden, MD † Jimmy J. Caudell, MD, PhD § University of Michigan John A. Ridge, MD, PhD ¶ Moffitt Cancer Center Comprehensive Cancer Center Fox Chase Cancer Center

Anthony J. Cmelak, MD § Vanderbilt-Ingram Cancer Center

Ying J. Hitchcock, MD † § Mucosal Melanoma Principles of Nutrition Huntsman Cancer Institute A. Dimitrios Colevas, MD †/Lead at the University of Utah Jatin P. Shah, MD, PhD ¶ Memorial Sloan Kettering Cancer Center Stanford Cancer Institute Loren K. Mell, MD § Paul M. Busse, MD, PhD § UC San Diego Moores Cancer Center Massachusetts General Hospital Cancer Center Bharat B. Mittal, MD § Robert H. Lurie Comprehensive Cancer Principles of Dental Evaluation and Management Ying J. Hitchcock, MD § Center of Northwestern University Frank Worden, MD † Huntsman Cancer Institute University of Michigan at the University of Utah Sue S. Yom, MD, PhD § Comprehensive Cancer Center UCSF Helen Diller Family Comprehensive Cancer Center

† Medical oncology ¶ Surgery/Surgical oncology § Radiation oncology Continue ξ Otolaryngology NCCN Guidelines Panel Disclosures Þ Internal medicine

NCCN Guidelines Version 1.2018 Table of Contents NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

NCCN Head Neck Cancers Panel Members Clinical Trials: NCCN believes that NCCN Head and Cancers Sub-Committee Members the best management for any patient Summary of the Guidelines Updates with cancer is in a clinical trial. Multidisciplinary Team and Support Services (TEAM-1) Participation in clinical trials is Cancer of the Lip (LIP-1) especially encouraged. Cancer of the Oral Cavity (OR-1) To find clinical trials online at NCCN Cancer of the Oropharynx (ORPH-1) Member Institutions, click here: • p16-negative (ORPH-2) nccn.org/clinical_trials/physician.html. • p16 (HPV)-positive (ORPHPV-1) NCCN Categories of Evidence and Cancer of the Hypopharynx (HYPO-1) Consensus: All recommendations Cancer of the Nasopharynx (NASO-1) are category 2A unless otherwise Cancer of the Glottic Larynx (GLOT-1) indicated. Cancer of the Supraglottic Larynx (SUPRA-1) See NCCN Categories of Evidence Ethmoid Sinus Tumors (ETHM-1) and Consensus. Maxillary Sinus Tumors (MAXI-1) Very Advanced Head and Neck Cancer (ADV-1) Recurrent/Persistent Head and Neck Cancer (ADV-3) Occult Primary (OCC-1) Salivary Gland Tumors (SALI-1) Mucosal Melanoma (MM-1) Follow-up Recommendations (FOLL-A) Principles of Surgery (SURG-A) Radiation Techniques (RAD-A) Principles of Systemic Therapy (CHEM-A) Principles of Nutrition: Management and Supportive Care (NUTR-A) Principles of Dental Evaluation and Management (DENT-A) Staging (ST-1)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2018.

NCCN Guidelines Version 1.2018 Updates NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Updates in Version 1.2018 of the NCCN Guidelines for Head and Neck Cancers from Version 2.2017 include: Global Changes Cancer of the Oral Cavity • The term "extracapsular spread" has been changed to "extranodal OR-2 extension." • First and second primary therapy options combined: "Resection • "Multimodality clinical trials" has been changed to "clinical trials." of primary (preferred) ± ipsilateral (guided by tumor thickness) or • "Lymphovascular invasion" has been changed to "vascular/ bilateral (guided by location of primary) neck dissection or SLN lymphatic invasion." biopsy" • For those with positive margins after resection, the adjuvant • Adjuvant therapy revised for those with extranodal extension ± therapy option of re-resection has been revised to "re-resection if positive margins: "Systemic therapy/RT (preferred) (category 1)" feasible," and the following footnote has been removed: "Consider OR-3 re-resection to achieve negative margins, if feasible." • Adjuvant therapy revised for those with extranodal extension ± TEAM-1 positive margins: "Systemic therapy/RT (preferred) (category 1) or • Under Multidisciplinary Team RT" Seventh bullet revised: "Physical medicine and rehabilitation • For those with positive margins, the adjuvant therapy options have (including therapy for lymphedema of the neck)" been revised to "Systemic therapy/RT (category 1) or re-resection if Twelfth bullet revised: "Diagnostic and interventional radiology" feasible and consider RT if negative margins or RT." OR-A (1 of 2) Cancer of the Lip • The following dose has been moved down, below concomitant LIP-2 boost accelerated RT: "66–70 Gy (2.0 Gy/fraction; 6 fractions/ • Treatment of Primary and Neck wk accelerated)." (Also on ORPH-A, HYPO-A, GLOT-A, SUPRA-A, The following has been moved from the primary therapy algorithm ETHM-A, MAXI-A, ADV-A) to a footnote: "Elective neck dissection not recommended." The following option and subsequent pathway have been Cancer of the Oropharynx removed: "Consider resection of primary ± sentinel lymph node ORPH-1 • Workup (SLN) biopsy (category 2B)" • Following surgical resection, a new pathway has been added for First bullet revised: "Tumor human papillomavirus (HPV) testing by p16 immunohistochemistry (IHC) recommended required" those with perineural/vascular/ lymphatic invasion, and RT is the recommended adjuvant therapy. Fifth bullet revised: "Consider FDG-PET/CT for stage III-IV disease" and moved under "as clinically indicated" LIP-3 • Observation has been added as an adjuvant therapy option for New pathways have been included for p16- disease versus HPV- patients with one positive node without adverse features. mediated (p16+) disease. • For those with extranodal extension and/or positive margins, the • Footnote "g" added: "The clinical staging definitions take into adjuvant therapy option of re-resection has been revised to "re- consideration the new AJCC 8th edition staging for oropharynx resection if feasible (for positive margin only)" and the following cancer, while referencing the staging criteria previously used in footnote has been removed: "Consider re-resection to achieve clinical trials on the management of oropharynx cancer." negative margins, if feasible." LIP-4 • Following therapy with definitive RT or systemic therapy/RT, imaging recommendations have been revised: "FDG-PET/CT (preferred) of primary and neck or CT of neck (with contrast)." Continued

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. UPDATES Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Updates NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Updates in Version 1.2018 of the NCCN Guidelines for Head and Neck Cancers from Version 2.2017 include: ORPH-2 HYPO-3 • The following primary treatment options has been revised: • Primary treatment option revised: "Partial or total "Transoral or open resection of primary ± ipsilateral or bilateral laryngopharyngectomy + neck dissection, including level VI, + neck dissection." thyroidectomy and pretracheal and ipsilateral paratracheal lymph "For T1-T2, N1 only, RT + systemic therapy (category 2B for node dissection" systemic therapy)." HYPO-5 • "Consider" removed for "systemic therapy/RT" for positive margins • Primary treatment option revised: "Surgery Total and other risk features. (Also on ORPH-3/4) laryngopharyngectomy + neck dissection + hemi- or total • Footnote removed: "The recommendations for patients at high thyroidectomy, and pretracheal and after ipsilateral or bilateral risk with extranodal extension + positive margins are based on paratracheal lymph node dissection" randomized studies involving patients for whom the HPV status of Cancer of the Nasopharynx their tumors was not specified." (Also on ORPH-3/4) NASO-1 ORPH-3 • Sixth bullet revised: "Imaging for distant metastases with FDG-PET/ • Footnote removed: When using concurrent systemic therapy/RT, the CT and/or chest CT with contrast, especially for nonkeratinizing preferred agent is cisplatin (category 1). See Principles of Systemic histology, endemic phenotype, or N2-3 disease; may be considered Therapy (CHEM-A). (Also on ORPH-4) for stage III-IV disease" ORPHPV-1 through ORPHPV-3 NASO-2 • Pages have been added with pathways for HPV-mediated (p16+) • Under primary treatment for T1, N1-3; T2-T4, any N, the category disease. 3 has been removed from the option of induction chemotherapy ORPH-A 1 of 2 category 3 followed by chemo/RT. (Also on CHEM-A, 1 of 5) • The last line has been revised: "Either IMRT (preferred) or 3D NASO-A conformal RT is recommended..." (Also on ORPH-A, 2 of 2) • Last line revised: "Either IMRT is (preferred) or over 3D conformal ORPH-B RT is recommended in for cancers of the nasopharynx to minimize • This page has been added, titled "Principles of p16 Testing for HPV- dose to critical structures. Proton therapy can be considered when Mediated Oropharyngeal Cancer." normal tissue constraints cannot be met by photon-based therapy." Cancer of the Hypopharynx Cancer of the Glottic Larynx HYPO-1 GLOT-1 • Under clinical stage, the first option revised:Most Amenable to • Under workup, last bullet revised: "Consider Pulmonary function larynx-preserving [conservation] surgery (Most T1, N0, and selected tests evaluation for conservation surgery candidates." T2, N0) (amenable to larynx-preserving [conservation] surgery) GLOT-3 • Second clinical staging pathway redefined: "T1-3, any N T2-3, Any N" • For N0,N1 disease after surgery, the following line has been added • Footnote removed: "Anatomical imaging is also recommended." to the primary treatment options: "...and pretracheal and ipsilateral HYPO-2 paratracheal lymph node dissection." • Second primary treatment option revised: "Surgery: Partial GLOT-4 laryngopharyngectomy (open or endoscopic) + ipsilateral or • After surgery, option revised: "Laryngectomy with thyroidectomy, bilateral neck dissection, + hemithyroidectomy, and pretracheal and as indicated, ipsilateral central, or bilateral neck dissection, and ipsilateral paratracheal lymph node dissection" pretracheal and ipsilateral paratracheal lymph node dissection" Continued

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. UPDATES Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Updates NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Updates in Version 1.2018 of the NCCN Guidelines for Head and Neck Cancers from Version 2.2017 include: GLOT-5 MAXI-3 • For primary site < PR, "surgery" changed to "laryngectomy." • Footnote removed: "For surgical resection, consider preoperative GLOT-6 RT or preoperative systemic therapy/RT in select patients • The following line has been added to the primary treatment options (category 2B)." for N0, N1, and N2-3 disease: "...and pretracheal and ipsilateral Very Advanced Head and Neck Cancer paratracheal lymph node dissection." ADV-2 • After primary treatment, pathways have been added to define the • For PS 0-1, the following primary treatment remains an option adjuvant therapy options for those with adverse features, and those but has been removed from this page since it is included in the with no adverse features. combination therapy options listed on CHEM-A (2 of 5): "Platinum Cancer of the Supraglottic Larynx + 5-FU + cetuximab (category 1)." (Also on ADV-4) SUPRA-2 ADV-3 • For positive margin, the adjuvant therapy option of re-resection has • The primary treatment options have been revised for those with been revised to: "Re-resection if feasible, in highly selected patients" a locoregional recurrence without prior RT, if resectable: Surgery or Concurrent systemic therapy/RT or Induction chemotherapy Ethmoid Sinus Tumors (category 3) followed by RT or systemic therapy/RT ETHM-2 • Footnote "c" added: "When using concurrent systemic therapy/ • Footnote "l" revised: "Adverse features include positive margins, RT, the preferred agent is cisplatin (category 1). See Principles of high-grade lesions, and intracranial extension (See Discussion)." Systemic Therapy (CHEM-A)." ETHM-3 ADV-A (1 of 2) • Following incomplete resection and no residual disease: • Line added to the chemoradiation section: "Data indicate that The following primary treatment option has been revised: "Surgery, accelerated fractionation does not offer improved efficacy over if feasible (See newly diagnosed T1,T2)." conventional fractionation." The following adjuvant therapy option has been added for those Ang K, Zhang Q, Wheeler RH, et al. A phase III trial (RTOG after primary treatment with surgery: "Consider systemic therapy/ 0129) of two radiation-cisplatin regimens for head and neck RT (category 2B) if adverse features." carcinomas (HNC): Impact of radiation and cisplatin intensity ETHM-A on outcome [abstract]. J Clin Oncol 2010;28(Suppl 15):Abstract • Last line revised: "Either IMRT is (preferred) or over 3D conformal 5507. RT is recommended for maxillary sinus or paranasal/ethmoid sinus Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy tumors to minimize dose to critical structures. The role of proton versus acceleration of radiotherapy with or without concomitant therapy is being investigated. Proton therapy can be considered chemotherapy in locally advanced head and neck carcinoma when normal tissue constraints cannot be met by photon-based (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet therapy." (Also on MAXI-A) Oncol 2012;13:145-153. Maxillary Sinus Tumors • Footnote "2", line added: "Proton therapy can be considered when MAXI-1 normal tissue constraints cannot be met by photon-based therapy. • Footnote "g" revised: "For sinonasal undifferentiated carcinoma (Takiar V, Garden AS, Ma D, et al. Reirradiation of head and neck (SNUC), small cell or sinonasal neuroendocrine carcinoma (SNEC) cancers with intensity modulated radiation therapy: Outcomes histologies, systemic therapy should be a part of the overall and analyses. Int J Radiat Oncol Biol Phys 2016;95:1117-1131.)" treatment. Consider a clinical trial and referral to a major medical center that specializes in these diseases." (Also on ETHM-1) Continued

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. UPDATES Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Updates NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Updates in Version 1.2018 of the NCCN Guidelines for Head and Neck Cancers from Version 2.2017 include: Occult Primary SALI-4 OCC-1 • The following recurrence therapy options have been added for those • Under workup, fourth bullet revised: "HPV, Epstein-Barr virus with distant metastases and PS 0-3: (EBV) testing suggested for squamous cell or undifferentiated "Androgen receptor therapy (ie. leuprolide, bicalutamide) if AR+ histology" Trastuzumab if HER2+ (category 2B)" OCC-2 • Footnote "m" added: "Check androgen receptor (AR) status and HER2 • Definitive treatment revised following evaluation of level IV or status prior to treatment for distant metastases." V adenocarcinoma of neck node for intraclavicular primary: SALI-A "Neck dissection if indicated ± adjuvant treatment if indicated • Last line added: "Proton therapy can be considered when normal (see OCC-4). Also, a link has been added to FOLL-A after tissue constraints cannot be met by photon-based therapy." treatment." • Footnote "2" revised: "Neutrons are still used in selected patients. OCC-3 Neutron therapy was historically considered a promising solution • Indications have been revised for the following treatment for unresectable salivary gland cancers, but this therapy is currently options: offered at only one center in the United States.Pfister DG, et al..." "Surgery Neck dissection (preferred for N1 disease, single • Footnote "5" added: In general, the reirradiated population of head node ≤3 cm)" and neck cancer patients described in current literature represents a "RT for N1, single node ≤3 cm (category 2B)" diverse but highly selected group of patients treated in centers where "Induction chemotherapy for N2-3 (category 3) followed by there is high level of expertise and systems in place for managing systemic therapy/RT or RT" acute and long-term toxicities. When the goal of treatment is curative Salivary Gland Tumors and surgery is not an option, reirradiation strategies can be considered SALI-3 for patients who: develop locoregional failures or second primaries • Cancer site descriptors have been revised: at ≥6 months after the initial radiotherapy; can receive additional Major salivary gland (parotid, submandibular, sublingual) doses of radiotherapy of at least 60 Gy; and can tolerate concurrent Minor salivary gland Sites chemotherapy. Organs at risk for toxicity should be carefully analyzed • Treatment option revised for majory salivary gland, clinical N0: through review of dose volume histograms, and consideration for "Parotidectomy Surgery with complete resection of tumor ± acceptable doses should be made on the basis of time interval since neck dissection for high-grade and/or T3-4 high-stage tumors" original radiotherapy, anticipated volumes to be included, and patient's • Treatment option revised for majory salivary gland, clinical N1: life expectancy. Proton therapy can be considered when normal tissue "Parotidectomy Surgery + neck dissection" constraints cannot be met by photon-based therapy. (Takiar V, Garden • Added "T3-4 tumors" to list of adverse features after complete AS, Ma D, et al. Reirradiation of head and neck cancers with intensity resection of a major salivary gland tumor. modulated radiation therapy: Outcomes and analyses. Int J Radiat • Adjuvant treatment options revised if adverse features after Oncol Biol Phys 2016;95:1117-1131.)" complete resection of a major salivary gland cancer: "Adjuvant RT (preferred) or consider systemic therapy/RT (category 2B)"

Continued

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. UPDATES Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Updates NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Updates in Version 1.2018 of the NCCN Guidelines for Head and Neck Cancers from Version 2.2017 include: Mucosal Melanoma Principles of Surgery MM-1 SURG-A (3 of 8) • Workup, fifth bullet revised: "Consider FDG-PET/CT scan or chest/ • Added to fifth bullet: If" carcinoma in situ is present and abdominal/pelvic CT with contrast, and brain MRI (with and without if additional margins can be obtained that is the favored contrast) to rule out metastatic disease" approach. Carcinoma in situ should not be considered an MM-2 indication for concurrent postoperative chemoradiation." • "Wide surgical resection" changed to "surgical resection." (Also on MM- SURG-A (5 of 8) 3) • Under neck management, first bullet revised: "Tumor sites MM-3 that frequently have bilateral lymphatic drainage (eg, base of • Primary treatment options revised for stage III disease: "Wide surgical tongue, palate, supraglottic larynx, hypopharynx, nasopharynx, resection, elective + neck dissection" deep pre-epiglottic..." MM-4 • Line revised: "Patients with advanced lesions involving • Additional therapy revised after nodal dissection: "± RT to nodal bed for the anterior tongue, floor of the mouth, orlip alveolus that high-risk features" approximate or cross the midline should undergo contralateral • Footnote "f" added: "High-risk, adverse features: >2 nodes, single node submandibular selective/modified neck dissection as >3 cm, extranodal extension, recurrence in nodal basin after previous necessary to achieve adequate tumor resection." surgery." SURG-A (6 of 8) MM-A • First bullet revised: "...Elective dissection depends on primary • Last two lines added: "Either IMRT or 3D conformal RT is recommended. tumor extent and site. Subglottic laryngeal cancers are sites Proton therapy can be considered when normal tissue constraints cannot where elective level VI dissections are often For advanced be met by photon-based therapy." glottic and hypopharyngeal cancers treated with primary surgery, a level VI dissection (including pretracheal lymph Follow-Up Recommendations nodes, the delphian lymph node, and unilateral or bilateral FOLL-A (1 of 2) paratracheal lymph nodes) and hemithyroidectomy to total • First line revised: "H&P exam (including a complete head and neck exam; thyroidectomy is appropriate. For primary subglottic tumors and mirror and fiberoptic examinationas clinically indicated)" or glottic cancers with significant subglottic extension, a • Imaging recommendations have been grouped together. level VI dissection with unilateral or total thyroidectomy is FOLL-A (2 of 2) considered appropriate based on the extent of the primary • Response after systemic therapy/RT or RT tumor. For example a T4a glottic tumor with extension through First bullet revised under assess extent of disease or distant metastases: the cricothyroid membrane and subglottic extension should "FDG-PET/CT (including CT + IV contrast) at minimum 12 wk" include a total thyroidectomy, and pretracheal and bilateral Added after FDT-PET/CT: "If imaging is positive, CT of primary and neck paratracheal lymph node dissection. Parathyroid glands should or MRI with contrast" be preserved in situ or auto transplanted as indicated."

Continued

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. UPDATES Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Updates NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Updates in Version 1.2018 of the NCCN Guidelines for Head and Neck Cancers from Version 2.2017 include: Radiation Techniques CHEM-A (2 of 5) RAD-A (2 of 5) • Gemcitabine/vinorelbine has been removed from the options for • Under IMRT, PBT and Fractionation, dosing revised in second nasopharyngeal cancer. sentence: The Simultaneous Integrated Boost (SIB) technique • Cisplatin/gemcitabine has been changed from a category 2A uses differential “dose painting” (66–72 74 Gy to gross disease; to a category 1 recommendation for recurrent, unresectable or 50–60 44–63 Gy to subclinical disease) for each fraction..." metastatic nasopharyngeal cancer. • Last line added under proton beam therapy: "Proton therapy can • New headings have been added to identify the first-line therapy be considered when normal tissue constraints cannot be met by options and second-line/subsequent therapy options. photon-based therapy." • Pembrolizumab has been added as a category 2B, second-line RAD-A (3 of 5) therapy option for nasopharyngeal cancer, if previously treated, • First heading revised: Palliative Radiation 3D Conformal RT, IMRT, PD-L1-positive recurrent or metastatic disease. and SBRT CHEM-A (3 of 5) through CHEM-A (5 of 5) • Seventh bullet added under reirradiation: "For 3D conformal RT • References have been updated. and IMRT: Standard dosing is 59.4–60 Gy at 1.8–2 Gy/fraction. Hyperfractionated schedule is 60 Gy at 1.2–1.5 Gy/fraction." Principles of Nutrition NUTR-A (1 of 2) Principles of Systemic Therapy • New section added for pain management with the following bullet CHEM-A (1 of 5) and references: Assess pain from oral mucositis and prescribe • Second bullet revised: "However, an improvement in overall gabapentin or doxepin as clinically indicated. survival with the incorporation of induction chemotherapy ◊◊Bar Ad V, Weinstein G, Dutta PR, et al. Gabapentin for the compared to proceeding directly to state-of-the-art concurrent treatment of pain syndrome related to radiation-induced chemoRT (cisplatin preferred, category 1) has not been mucositis in patients with head and neck cancer treated with established in randomized phase III studies. comparing sequential concurrent chemoradiotherapy. Cancer 2010;116:4206-4213. chemotherapy/RT to concurrent chemotherapy/RT alone are ◊◊Leenstra JL, Miller RC, Qin R, et al. Doxepin rinse versus ongoing and have not demonstrated a convincing survival benefit placebo in the treatment of acute oral mucositis pain in with the incorporation of induction chemotherapy." patients receiving head and neck radiotherapy with or without • Third sub-bullet revised under induction/sequential chemotherapy chemotherapy: a phase III, randomized, double-blind trial for cancer of the Lip, Oral Cavity, Oropharynx, Hypopharynx, (NCCTG-N09C6 [Alliance]). J Clin Oncol 2014;32:1571-1577. Glottic Larynx, Supraglottic Larynx, Ethmoid Sinus, Maxillary Sinus, Occult Primary: "Following induction, agents to be Staging used with concurrent chemoradiation typically include weekly ST-1 carboplatin, weekly cisplatin (category 2B), or weekly cetuximab." • Staging tables have been updated to reflect the AJCC 8th Edition Cancer Staging System.

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. UPDATES Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Team Approach Discussion

MULTIDISCIPLINARY TEAM The management of patients with head and neck cancers is complex. All patients need access to the full range of support services and specialists with expertise in the management of patients with head and neck cancer for optimal treatment and follow-up. Outcomes are improved when patients with head and neck cancers are treated in high-volume centers. • Head and neck surgery • Clinical nutrition • Radiation oncology • Pathology (including cytopathology) • Medical oncology • Diagnostic and interventional radiology • Plastic and reconstructive surgery • Adjunctive services • Specialized nursing care Neurosurgery • Dentistry/prosthodontics Ophthalmology • Physical medicine and rehabilitation Psychiatry (including therapy for lymphedema of the Addiction services neck) Audiology • Speech and swallowing therapy Palliative care • Clinical social work

SUPPORT SERVICES Follow-up should be performed by a physician and other health care professionals with expertise in the management and prevention of treatment sequelae. It should include a comprehensive head and neck exam. The management of head and neck cancer patients may involve the following: • General medical care • Speech and swallowing therapy • Pain and symptom management • Audiology (See NCCN Guidelines for Adult Cancer Pain) • Tracheotomy care • Nutritional support • Wound management Enteral feeding • Depression assessment and management Oral nutrition (See NCCN Guidelines for Distress • Dental care for RT effects Management) • Xerostomia management • Social work and case management • Smoking and alcohol cessation • Supportive care (See NCCN Guidelines for Smoking Cessation) (See NCCN Guidelines for Palliative Care)

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. TEAM-1 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Lip Discussion

WORKUP CLINICAL STAGING

T1-2, N0 See Treatment of Primary and Neck (LIP-2)

• History and physical (H&P)a,b including a complete head and Surgical neck exam; mirror and/or fiberoptic See Treatment of Primary and Neck (LIP-3) examination as clinically indicated candidate T3, T4a, N0 • Biopsy Any T, N1-3 • Chest CT (with or without contrast) c Unfit for as clinically indicated surgery • As indicated for primary evaluation Panorex See Treatment of Very Advanced Head and Neck CT and/or MRI with contrast of Cancer (ADV-1) primary and neck T4b, any N, or • Preanesthesia studies as clinically unresectable nodal indicated disease • Dental evaluationd

Multidisciplinary consultation as indicated Metastatic (M1) disease at See Treatment of Very Advanced Head and Neck initial presentation Cancer (ADV-2)

aH&P should include documentation and quantification (pack years smoked) of tobacco use history. Smoking cessation counseling as clinically indicated. All current smokers should be advised to quit smoking, and former smokers should be advised to remain abstinent from smoking. For additional cessation support and resources, smokers can be referred to the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. bScreen for depression (See NCCN Guidelines for Distress Management). cChest CT is recommended for advanced nodal disease to screen for distant metastases, and for select patients who smoke to screen for lung cancer. See NCCN Guidelines for Lung Cancer Screening. dSee Principles of Dental Evaluation and Management (DENT-A).

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. LIP-1 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Lip Discussion

CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT FOLLOW-UP STAGING TREATMENT

Re-resection, if feasible Positive margin or g RT Recurrent Follow-up or Perineural/vascular/ Surgical resection (preferred)e,f RTg (See persistent lymphatic invasion FOLL-A) disease (See ADV-3)

No adverse pathologic findings No positive nodes

T1-2, N0 or

Definitive RT to Treatment of Primary and Neck (LIP-4) primary siteg,h

eElective neck dissection is not recommended. fSee Principles of Surgery (SURG-A). gSee Principles of Radiation Therapy (LIP-A). hNo elective treatment to neck is preferred for the T1-2, N0.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Lip Discussion

CLINICAL STAGING: TREATMENT OF PRIMARY AND NECK ADJUVANT FOLLOW-UP T3, T4a, N0; Any T, N1-3 TREATMENT

Resection of primary N0 N0 ± ipsilateral or bilateral neck dissectionf

RTg (optional) N1, Resection of primary, One positive node without Surgeryf j or N2a-b, ipsilateral neck dissection adverse features (preferred) Observation N3 ± contralateral neck dissectionf Systemic therapy/ RTg,i preferred Follow-up (category 1) (See FOLL-A) N2c Resection of primary and Extranodal or (bilateral) bilateral neck dissectionf extension and/ Re-resection, or positive if feasible (for margin positive margin only) Recurrent or persistent or Adverse or g disease featuresj RT (See ADV-3) Definitive RTg or RTg Treatment of Primary and Neck (LIP-4) Systemic or Other risk therapy/RTg,i Consider features systemic therapy/RTg,i

fSee Principles of Surgery (SURG-A). gSee Principles of Radiation Therapy (LIP-A). iSee Principles of Systemic Therapy (CHEM-A). jAdverse features: extranodal extension, positive margins, multiple positive nodes, or perineural/lymphatic/vascular invasion.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Lip Discussion

CLINICAL STAGING: TREATMENT OF PRIMARY AND NECK FOLLOW-UP T3, T4a, N0; Any T, N1-3

Primary site: Complete clinical Follow-up response (See FOLL-A) (N0 at initial staging)

FDG-PET/CT (preferred) of Primary site: Recurrent Definitive RTf primary and Complete or or neck See Follow-Up Recommendations Post clinical persistent Systemic or Chemoradiation or RT (FOLL-A, 2 of 2) response (N+ at disease therapy/RTf,i CT of initial staging) (See ADV-3) neck (with contrast)

Primary site: < complete Surgery + neck Follow-up clinical dissection as indicatede (See FOLL-A) response

eSee Principles of Surgery (SURG-A). fSee Principles of Radiation Therapy (LIP-A). iSee Principles of Systemic Therapy (CHEM-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Lip Discussion

PRINCIPLES OF RADIATION THERAPY1

DEFINITIVE: POSTOPERATIVE: RT Alone RT • Planning target volume (PTV) • Preferred interval between resection and postoperative RT is High risk: Primary tumor and involved lymph nodes (this includes ≤6 weeks. possible local subclinical infiltration at the primary site and at the • PTV high-risk level lymph node(s)) High risk: Adverse features such as positive margins ◊◊66 Gy (2.2 Gy/fraction) to 70 Gy (2.0 Gy/fraction); daily (see footnote j on LIP-3) Monday–Friday in 6–7 weeks2 ◊◊60–66 Gy (2.0 Gy/fraction) daily Monday–Friday in 6–6.5 weeks Low to intermediate risk: Sites of suspected subclinical spread Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)3 ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)3 • External beam RT (EBRT) ± brachytherapy4,5 • For T1-T2 simple lesions, treat with postoperative RT as per • Brachytherapy non-melanoma skin cancers. See NCCN Guidelines for Non- Interstitial brachytherapy is considered for selected cases.4,5 Melanoma Skin Cancer ◊◊Low dose-rate (LDR) brachytherapy (0.4–0.5 Gy per hour): ––Consider LDR boost 20–35 Gy if combined with 50 Gy EBRT or 60–70 Gy over several days if using LDR as sole therapy ◊◊High dose-rate (HDR) brachytherapy: ––Consider HDR boost 21 Gy at 3 Gy/fraction if combined with 40–50 Gy EBRT or 45–60 Gy at 3–6 Gy/fraction if using HDR as sole therapy.

Either intensity-modulated RT (IMRT) or 3D conformal RT is recommended.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oral Cavity Discussion

Buccal mucosa, floor of mouth, anterior tongue, alveolar ridge, retromolar trigone, hard palate WORKUP CLINICAL STAGING

• H&Pa,b including a complete head T1-2, N0 See Treatment of Primary and Neck (OR-2) and neck exam; mirror and fiberoptic examination as clinically indicated • Biopsy • Chest CT (with or without contrast) as clinically indicatedc T3, N0 • CT with contrast and/or MRI with contrast of primary and neck as indicated • Consider FDG-PET/CT for stage III-IV diseased T1-3, N1-3 See Treatment of Primary and Neck (OR-3) • Examination under anesthesia (EUA) with endoscopy, if indicated • Preanesthesia studies as clinically indicated T4a, any N • Dental/prosthodontic evaluation,e including Panorex or dental CT without contrast as clinically indicated T4b, any N, • Nutrition, speech and swallowing or See Treatment of Very Advanced Head and Neck evaluation/therapy as indicatedf Unresectable nodal disease Cancer (ADV-1) or • Multidisciplinary consultation as indicated Unfit for surgery

Metastatic (M1) disease See Treatment of Very Advanced Head and Neck at initial presentation Cancer (ADV-2)

aH&P should include documentation and quantification (pack years smoked) of tobacco cChest CT is recommended for advanced nodal disease to screen for use history. Smoking cessation counseling as clinically indicated. All current smokers distant metastases, and for select patients who smoke to screen for lung should be advised to quit smoking, and former smokers should be advised to remain cancer. See NCCN Guidelines for Lung Cancer Screening. abstinent from smoking. For additional cessation support and resources, smokers can be dSee Discussion. referred to the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. eSee Principles of Dental Evaluation and Management (DENT-A). bScreen for depression (See NCCN Guidelines for Distress Management). fSee Principles of Nutrition: Management and Supportive Care (NUTR-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oral Cavity Discussion

Buccal mucosa, floor of mouth, anterior tongue, alveolar ridge, retromolar trigone, hard palate CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT FOLLOW-UP STAGING No positive nodes and No adverse featuresj SLN pN0 SLN identification Resection One positive node successful Consider RTi of primary without adverse featuresj (preferred) SLN pN+ ± ipsilateral Extranodal Follow-up Systemic therapy/RTi,k (guided by tumor extension ± (See FOLL-A) (category 1) thickness) or positive margin T1–2, bilateral (guided Re-resection, if feasible N0 by location of or Recurrent primary) neck Adverse Positive RTi or g j dissection or features margin or persistent SLN biopsyh SLN Consider systemic Neck disease identification therapy/RTi,k dissectiong (See ADV-3) unsuccessful RTi Other risk or features Consider systemic therapy/RTi,k or

See Follow-Up Recommendations Post Definitive RTi Recurrent or persistent Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3)

jAdverse risk features: extranodal extension, positive margins, pT3 or pT4 gSee Principles of Surgery (SURG-A). primary, N2 or N3 nodal disease, nodal disease in levels IV or V, perineural hSee Sentinel Lymph Node Biopsy in Principles of Surgery [SURG-A 6 of 8]. invasion, vascular embolism, lymphatic invasion (See Discussion). iPrinciples of Radiation Therapy (OR-A). kSee Principles of Systemic Therapy (CHEM-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oral Cavity Discussion

Buccal mucosa, floor of mouth, anterior tongue, alveolar ridge, retromolar trigone, hard palate CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT FOLLOW-UP STAGING TREATMENT

No adverse Consider RTi N0, N1, Resection of primary, featuresj N2a-b, ipsilateral, or bilateral N3 neck dissectiong Extranodal extension Systemic therapy/ ± positive RTi,k (category 1) margin Surgeryg

T3,N0; Systemic therapy/ Resection of primary i,k Follow-up T1-3, N1-3; or N2c RT (category 1) T4a, Any N and bilateral neck or (See FOLL-A) (bilateral) g Adverse Positive dissection Re-resection, featuresj margin if feasible and Clinical trials consider RT if Recurrent negative margins or persistent i disease RT (See ADV-3) Other risk or features Consider systemic therapy/RTi,k

gSee Principles of Surgery (SURG-A). iSee Principles of Radiation Therapy (OR-A). jAdverse risk features: extranodal extension, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, vascular embolism, lymphatic invasion (See Discussion). kSee Principles of Systemic Therapy (CHEM-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oral Cavity Discussion

PRINCIPLES OF RADIATION THERAPY1 DEFINITIVE: RT Alone • PTV: High risk: Primary tumor and involved lymph nodes (this includes possible local subclinical infiltration at the primary site and at the high-risk level lymph node(s)): ◊◊Fractionation: ––66 Gy (2.2 Gy/fraction) to 70 Gy (2.0 Gy/fraction); daily Monday–Friday in 6–7 weeks2 ––Concomitant boost accelerated RT: ––72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) ––66–70 Gy (2.0 Gy/fraction; 6 fractions/wk accelerated) ––Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)3 • Brachytherapy Interstitial brachytherapy is considered for selected cases.4,5 ◊◊LDR brachytherapy (0.4–0.5 Gy per hour): ––Consider LDR boost 20–35 Gy if combined with 50 Gy EBRT or 60–70 Gy over several days if using LDR as sole therapy. ◊◊HDR brachytherapy: ––Consider HDR boost 21 Gy at 3 Gy/fraction if combined with 40–50 Gy EBRT or 45–60 Gy at 3–6 Gy/fraction if using HDR as sole therapy.

For unresectable disease, see ADV-1. Either IMRT or 3D conformal RT is recommended.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. OR-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oral Cavity Discussion

PRINCIPLES OF RADIATION THERAPY1

POSTOPERATIVE: RT • Preferred interval between resection and postoperative RT is ≤6 weeks. • PTV High risk: Adverse features such as positive margins (see footnote j on OR-3) ◊◊60–66 Gy (2.0 Gy/fraction); daily Monday–Friday in 6–6.5 weeks Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)3

POSTOPERATIVE CHEMORADIATION: • Concurrent systemic therapy6-10

Either IMRT or 3D conformal RT is recommended.

1See Radiation Techniques (RAD-A) and Discussion. 3Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). 6See Principles of Systemic Therapy (CHEM-A). 7Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952. 8Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-1944. 9Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843-850. 10Cooper JS, Zhang Q, Pajak TF et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012;84:1198-1205.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. OR-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oropharynx Discussion

Base of tongue/tonsil/posterior pharyngeal wall/soft palate WORKUP CLINICAL STAGINGg TREATMENT T1-2, N0-1 See ORPH-2 • Tumor human papillomavirus (HPV) testing by p16 immunohistochemistry T3-4a, N0-1 See ORPH-3 (IHC) requireda • H&Pb,c including a complete head p16- Any T, N2-3 See ORPH-4 negative and neck exam; mirror and fiberoptic T4b, any N examination as clinically indicated or See Treatment of Very Advanced Unresectable nodal disease • Biopsy of primary site or fine-needle Head and Neck Cancer (ADV-1) aspiration (FNA) of the neck or • CT with contrast and/or MRI with Unfit for surgery contrast of primary and neck See Treatment of Very Advanced Metastatic (M1) disease initial presentation • Preanesthesia studies Head and Neck Cancer (ADV-2) • As clinically indicated: FDG-PET/CT T1-2, N0-1 (single node ≤3 cm) See ORPHPV-1 Chest CTd (with or without contrast) e Dental evaluation, including Panorex T3-4, N0-1 (single node ≤3 cm) See ORPHPV-2 Nutrition, speech and swallowing evaluation/therapy, and audiogramf p16 (HPV)- Any T, N1 (single node >3 cm, or 2 or EUA with endoscopy See ORPHPV-3 positive more ipsilateral nodes ≤6 cm), N2-3

Multidisciplinary consultation as See Treatment of Very Advanced Unresectable or unfit for surgery clinically indicated Head and Neck Cancer (ADV-1) See Treatment of Very Advanced Metastatic (M1) disease initial presentation Head and Neck Cancer (ADV-2) aSee Principles of p16 Testing and HPV Status (ORPH-B). dChest CT is recommended for advanced nodal disease to screen for distant bH&P should include documentation and quantification (pack years metastases, and for select patients who smoke to screen for lung cancer. See smoked) of tobacco use history. Smoking cessation counseling as NCCN Guidelines for Lung Cancer Screening. clinically indicated. All current smokers should be advised to quit smoking, eSee Principles of Dental Evaluation and Management (DENT-A). and former smokers should be advised to remain abstinent from smoking. fSee Principles of Nutrition: Management and Supportive Care (NUTR-A). For additional cessation support and resources, smokers can be referred gThe clinical staging definitions take into consideration the new AJCC 8th edition to the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. staging for oropharynx cancer, while referencing the staging criteria previously cScreen for depression (See NCCN Guidelines for Distress Management). used in clinical trials on the management of oropharynx cancer.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oropharynx (p16-negative) Discussion

Base of tongue/tonsil/posterior pharyngeal wall/soft palate CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING See Follow-Up Recommendations Post Recurrent or persistent Definitive RTi Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3)

or No adverse featuresl

Extranodal Transoral or open extension ± Systemic therapy/RTi,k resection of primary positive margin ± neck dissectionj Recurrent Re-resection, if feasible or (preferred) Follow-up persistent or (See FOLL-A) Adverse Positive margin g disease featuresl RT p16-negative or (See ADV-3) T1-2, N0-1 Systemic therapy/RTi,k or g Other risk RT or features Systemic therapy/RTi,k

For T1-2, N1 only: See Follow-Up Recommendations Post Recurrent or persistent RTi + systemic therapyk (category Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3) 2B for systemic therapy) or Clinical trials

iSee Principles of Radiation Therapy (ORPH-A). jSee Principles of Surgery (SURG-A). kSee Principles of Systemic Therapy (CHEM-A). lAdverse features: extranodal extension, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, vascular embolism, lymphatic invasion (See Discussion).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oropharynx (p16-negative) Discussion

Base of tongue/tonsil/posterior pharyngeal wall/soft palate CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING

Concurrent See Follow-Up Recommendations Post Recurrent or persistent systemic Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3) therapy/RTi,k

or No adverse featuresl RTi

Transoral Extranodal or open extension and/ i,k Recurrent resection Systemic therapy/RT or or positive Follow-up for primary persistent j margin (See FOLL-A) and neck disease p16-negative Adverse (See ADV-3) T3-4a, N0-1 featuresl or RTg Other risk or features i,k Induction Systemic therapy/RT chemotherapy (category 3)k,m See Follow-Up Recommendations Post Recurrent or persistent followed by RTi Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3) or systemic therapy/RTi,k or Clinical trials

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oropharynx (p16-negative) Discussion

Base of tongue/tonsil/posterior pharyngeal wall/soft palate CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING Concurrent systemic therapy/RTi,k or See Follow-Up Recommendations Post Recurrent or persistent Induction Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3) chemotherapyk,m (category 3) followed by RTi or systemic therapy/RTi,k p16-negative No adverse Any T, N2-3 or Resection of primary, featuresl N2a-b ipsilateral, or bilateral Follow-up Transoral N3 neck dissectionj (See FOLL-A) or open Extranodal resection:j extension and/ Systemic i,k Primary and Resection of or positive therapy/RT neck N2c primary and bilateral margin Recurrent neck dissectionj Adverse featuresl or RTi or persistent or Other risk disease Systemic Clinical trials features (See ADV-3) therapy/RTi,k

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oropharynx (p16 [HPV]-positive) Discussion

Base of tongue/tonsil/posterior pharyngeal wall/soft palate CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGINGn See Follow-Up Recommendations Post Recurrent or persistent Definitive RTi Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3)

or No adverse featuresn,o,p Transoral or open resection Extranodal Systemic therapy/RTi,k,q of primary extensionp ± or ± ipsilateral or positive margin RT (category 2B) Recurrent bilateral neck Re-resection, if feasible or dissectionj Follow-up or persistent Adverse i,k (See FOLL-A) n,o,p Positive margin Systemic therapy/RT disease features or (See ADV-3) p16 (HPV)-positive RTi (category 2B) cT1-2, cN0-1 or (single node ≤3 cm) RTi Other risk or featureso,p Systemic therapy/RTi,k (category 2B) For T2, single node ≤3 cm, RTi + systemic See Follow-Up Recommendations Post Recurrent or persistent therapyk (category 2B Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3) for systemic therapy)

or Clinical trials oIn the event of pathologic upstaging, continue to appropriate algorithm. pAdverse features: extranodal extension, positive margins, nodal disease in levels IV or V, iSee Principles of Radiation Therapy (ORPH-A). perineural invasion, vascular embolism, lymphatic invasion (See Discussion). The definition jSee Principles of Surgery (SURG-A). of an adverse feature in the context of HPV+ disease is an area of active research. This kSee Principles of Systemic Therapy (CHEM-A). includes the presence and extent of ENE, and the number of involved nodes. nPathologic staging criteria differ from clinical staging criteria in HPV- qThe recommendations for patients at high risk with extranodal extension + positive margins mediated oropharyngeal cancer. For pathologic stage following are based on randomized studies involving patients for whom the HPV status of their resection, see AJCC 8th edition for appropriate staging criteria (ST-7). tumors was not specified.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oropharynx (p16 [HPV]-positive) Discussion

Base of tongue/tonsil/posterior pharyngeal wall/soft palate CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING

Concurrent See Follow-Up Recommendations Post Recurrent or persistent systemic Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3) therapy/RTi,k or No adverse RTi featuresn,o,p Transoral or open resection Extranodal p i,k,q Recurrent for primary and extension and/or Systemic therapy/RT or j Follow-up neck positive margin persistent (See FOLL-A) Adverse disease p16 (HPV)-positive featuresn,o,p (See ADV-3) cT3-4, cN0-1 or RTi Other risk (single node ≤3 cm) n,o,p or features i,k Induction Systemic therapy/RT chemotherapy (category 3)k,m See Follow-Up Recommendations Post Recurrent or persistent followed by RTi Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3) or systemic therapy/RTi,k or Clinical trials

iSee Principles of Radiation Therapy (ORPH-A). jSee Principles of Surgery (SURG-A). pAdverse features: extranodal extension, positive margins, nodal disease in levels IV or V, kSee Principles of Systemic Therapy (CHEM-A). perineural invasion, vascular embolism, lymphatic invasion (See Discussion). The definition mSee Discussion on induction chemotherapy. of an adverse feature in the context of HPV+ disease is an area of active research. This nPathologic staging criteria differ from clinical staging criteria in HPV- includes the presence and extent of ENE, and the number of involved nodes. mediated oropharyngeal cancer. For pathologic stage following qThe recommendations for patients at high risk with extranodal extension + positive margins resection, see AJCC 8th edition for appropriate staging criteria (ST-7). are based on randomized studies involving patients for whom the HPV status of their oIn the event of pathologic upstaging, continue to appropriate algorithm. tumors was not specified.

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ORPHPV-2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oropharynx (p16 [HPV]-positive) Discussion

Base of tongue/tonsil/posterior pharyngeal wall/soft palate CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING Concurrent systemic therapy/RTi,k See Follow-Up or Recommendations Recurrent or persistent Induction Post Chemoradiation k,m disease (See ADV-3) chemotherapy or RT (FOLL-A, 2 of 2) (category 3) followed by RTi p16 (HPV)-positive or systemic i,k Any T, cN1 (single therapy/RT node >3 cm, or 2 or or more ipsilateral No adverse cN1-cN3 Resection of n,o,p nodes ≤6 cm), cN2-3 features Follow-up Transoral or (unilateral) primary, neck j Extranodal (See FOLL-A) open dissection extension and/ Systemic resection:j or positive therapy/RTi,k,q Primary and Resection of cN2-3 margin neck primary and (bilateral) i Recurrent bilateral neck Adverse RT or j featuresn,o,p or or dissection Other risk Consider persistent featuresn,p Clinical trials systemic disease therapy/RTi,k (See ADV-3)

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ORPHPV-3 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oropharynx Discussion

PRINCIPLES OF RADIATION THERAPY1 DEFINITIVE: CONCURRENT CHEMORADIATION:5,6 RT Alone • PTV: • PTV High risk: Typically 70 Gy (2.0 Gy/fraction) High risk: Primary tumor and involved lymph nodes (this includes Low to intermediate risk: 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy possible local subclinical infiltration at the primary site and at the (1.6–1.8 Gy/fraction)4 high-risk level lymph node(s) ◊◊Fractionation: ––66 Gy (2.2 Gy/fraction) to 70 Gy (2.0 Gy/fraction); daily Monday–Friday in 6–7 weeks2 ––Concomitant boost accelerated RT: ▪▪72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) ▪▪66–70 Gy (2.0 Gy/fraction; 6 fractions/wk accelerated) ––Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) ––69.96 Gy (2.12 Gy/fraction) daily Monday–Friday in 6–7 weeks3 Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4

Either IMRT (preferred) or 3D conformal RT is recommended for cancers of the oropharynx in order to minimize dose to critical structures.

1See Radiation Techniques (RAD-A) and Discussion. 2For doses >70 Gy, some clinicians feel that the fractionation should be slightly modified (eg, <2.0 Gy/fraction for at least some of the treatment) to minimize toxicity. An additional 2–3 doses can be added depending on clinical circumstances. 3Eisbruch A, Harris J, Garden AS, et al. Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol Biol Phys 2010;76:1333-1338. 4Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). 5See Principles of Systemic Therapy (CHEM-A). 6Based on published data, concurrent chemoradiation most commonly uses conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with single-agent cisplatin given every 3 weeks at 100 mg/m2; 2–3 cycles of chemotherapy are used depending on the radiation fractionation scheme (RTOG 0129) (Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24-35). When carboplatin and 5-FU are used, the recommended regimen is standard fractionation plus 3 cycles of chemotherapy. (Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol 2012;13:145-153). Other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, other dosing schedules of cisplatin, or altered fractionation with chemotherapy are efficacious, and there is no consensus on the optimal approach. In general, the use of concurrent chemoradiation carries a high toxicity burden; altered fractionation or multiagent chemotherapy will likely further increase the toxicity burden. For any chemoradiation approach, close attention should be paid to published reports for the specific chemotherapy agent, dose, and schedule of administration. Chemoradiation should be performed by an experienced team and should include substantial supportive care.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. ORPH-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oropharynx Discussion

PRINCIPLES OF RADIATION THERAPY1

POSTOPERATIVE: RT • Preferred interval between resection and postoperative RT is ≤6 weeks. • PTV High risk: Adverse features such as positive margins (See footnote l on ORPH-3) ◊◊60–66 Gy (2.0 Gy/fraction); daily Monday–Friday in 6–6.5 weeks Low to intermediate risk: sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4

POSTOPERATIVE CHEMORADIATION: • Concurrent systemic therapy7-11 Either IMRT (preferred) or 3D conformal RT is recommended for cancers of the oropharynx in order to minimize dose to critical structures.

1See Radiation Techniques (RAD-A) and Discussion. 4Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent upon dose per fraction). 7See Principles of Systemic Therapy (CHEM-A). 8Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952. 9Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-1944. 10Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843-850. 11Cooper JS, Zhang Q, Pajak TF et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012;84:1198-1205.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. ORPH-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Oropharynx Discussion

PRINCIPLES OF P16 TESTING FOR HPV-MEDIATED OROPHARYNGEAL CANCER • P16 expression is highly correlated with HPV status and prognosis and is widely available. • A few HPV testing options are available for use in the clinical setting. Expression of p16 as detected by IHC is a widely available surrogate biomarker that has very good agreement with HPV status as determined by the gold standard of HPV E6/E7 mRNA expression.1-3 Other tests include HPV detection through PCR and in situ hybridization (ISH).1,3 • Sensitivity of IHC staining for p16 and PCR-based assay is high, although specificity is highest for ISH.3 • Due to variations in sensitivity and specificity values of testing options, multiple methods may be used in combination for HPV detection, but HPV detection through PCR and ISH may provide additional sensitivity for the former and specificity for the latter in the case of an equivocal p16 or unclear clinical scenario.3-6 • Sufficient pathologic material for HPV testing can be obtained through FNA.6,7 • A small proportion of tumors at non-oropharyngeal sites (eg, paranasal sinus, oral cavity, larynx) are HPV-related. However, given the small proportion and lack of consistent evidence in support of prognostic significance, routine HPV testing or p16 tseting of non-oropharyngeal cancers is not recommended. • Guidelines for testing are available from the College of American Pathologists.8

1Jordan RC, Lingen MW, Perez-Ordonez B, et al. Validation of methods for oropharyngeal cancer HPV status determination in US cooperative group trials. Am J Surg Pathol 2012;36:945-954. 5Thavaraj S, Stokes A, Guerra E, et al. Evaluation of human papillomavirus testing for 2Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification squamous cell carcinoma of the tonsil in clinical practice. J Clin Pathol 2011;64:308- identifies a subset of human papillomavirus–associated oropharyngeal 312. cancers with favorable prognosis. J Clin Oncol 2006;24:736-747. 6Snow AN, Laudadio J. Human papillomavirus detection in head and neck squamous 3Cantley RL, Gabrielli E, Montebelli F, et al. Ancillary studies in cell carcinomas. Adv Anat Pathol 2010;17:394-403. determining human papillomavirus status of squamous cell carcinoma 7Begum S, Gillison ML, Nicol TL, Westra WH. Detection of human papillomavirus-16 in of the oropharynx: a review. Patholog Res Int 2011;2011:138469. fine-needle aspirates to determine tumor origin in patients with metastatic squamous 4Singhi AD, Westra WH. Comparison of human papillomavirus in cell carcinoma of the head and neck. Clin Cancer Res 2007;13:1186-1191. situ hybridization and p16 immunohistochemistry in the detection of 8Lewis JS, Jr., Beadle B, Bishop JA, et al. Human papillomavirus testing in head and human papillomavirus-associated head and neck cancer based on a neck carcinomas: Guideline from the College of American Pathologists. Arch Pathol prospective clinical experience. Cancer 2010;116:2166-2173. Lab Med 2017.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Hypopharynx Discussion

WORKUP CLINICAL STAGING

Amenable to larynx-preserving See Treatment of Primary and [conservation] surgery (most Neck (HYPO-2) • H&Pa,b including a complete head and T1, N0, and selected T2, N0) neck exam; mirror and/or fiberoptic examination as clinically indicated • Biopsy of primary site or FNA of neck T1-3, any N; See Treatment of Primary and • Chest CT (with or without contrast) as Neck (HYPO-3) clinically indicatedc Advanced cancer requiring • CT with contrast and/or MRI with (amenable to) pharyngectomy contrast of primary and neck with total laryngectomy • Consider FDG-PET/CT for stage III-IV See Treatment of Primary and T4a, Any N disease Neck (HYPO-5) • EUA with endoscopy • Preanesthesia studies as clinically indicated T4b, any N • Nutrition, speech and swallowing or See Treatment of Very evaluation/therapy, and audiogram as Unresectable nodal disease Advanced Head and Neck clinically indicatedd or Cancer (ADV-1) • Dental evaluatione Unfit for surgery • Consider pulmonary function tests for conservation surgery candidates Multidisciplinary consultation as See Treatment of Very clinically indicated Metastatic (M1) disease Advanced Head and Neck at initial presentation Cancer (ADV-2)

aH&P should include documentation and quantification (pack years smoked) of tobacco use history. Smoking cessation counseling as clinically indicated. All current smokers cChest CT is recommended for advanced nodal disease to screen for should be advised to quit smoking, and former smokers should be advised to remain distant metastases, and for select patients who smoke to screen for lung abstinent from smoking. For additional cessation support and resources, smokers can cancer. See NCCN Guidelines for Lung Cancer Screening. be referred to the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. dSee Principles of Nutrition: Management and Supportive Care (NUTR-A). bScreen for depression (See NCCN Guidelines for Distress Management). eSee Principles of Dental Evaluation and Management (DENT-A).

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. HYPO-1 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Hypopharynx Discussion

CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING

See Follow-Up Recommendations Post Recurrent or persistent Definitive RTf Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3)

or No adverse featuresh Most T1, N0, Partial laryngopharyngectomy Extranodal Systemic selected T2, N0 f,i (amenable (open or endoscopic) extension therapy/RT to larynx- + ipsilateral or bilateral ± positive margin (category 1) preserving neck dissection, + [conservation] hemithyroidectomy, Re-resection, if surgery) and pretracheal and feasible ipsilateral paratracheal or Recurrent g f or lymph node dissection Adverse RT Follow-up h Positive margin Persistent features or (See FOLL-A) Consider systemic Disease f,i (See ADV-3) or therapy/RT (for T2 only) RTf Clinical trials Other risk or features Consider systemic therapy/RTf,i

fSee Principles of Radiation Therapy (HYPO-A). gSee Principles of Surgery (SURG-A). hAdverse features: extranodal extension, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease, perineural invasion, vascular embolism, lymphatic invasion (See Discussion). iSee Principles of Systemic Therapy (CHEM-A).

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. HYPO-2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Hypopharynx Discussion

CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING CT or MRI (with contrast) See Response After Induction Induction chemotherapyi,j of primary and neck Chemotherapy (HYPO-4) or

No adverse Partial or total h laryngopharyngectomy features + neck dissection Extranodal f,i + thyroidectomy extension and/or Systemic therapy/RT Follow-up and pretracheal and positive margin (category 1) (See FOLL-A) T2-3, any N ipsilateral paratracheal Adverse (if requiring f lymph node dissectiong featuresh RT [amenable to] Other risk or pharyngectomy features Consider systemic Recurrent with partial therapy/RTf,i or or total persistent laryngectomy); or disease T1, N+ (See ADV-3) See Follow-Up Recommendations Concurrent systemic Recurrent or persistent disease f,i,k Post Chemoradiation or RT therapy/RT (FOLL-A, 2 of 2) (See ADV-3)

Clinical trials

fSee Principles of Radiation Therapy (HYPO-A). gSee Principles of Surgery (SURG-A). iSee Principles of Systemic Therapy (CHEM-A). hAdverse features: extranodal extension, positive margins, pT3 jIn randomized clinical trials, assessment of response has been done after 2 or 3 cycles. or pT4 primary, N2 or N3 nodal disease, perineural invasion, kWhen using concurrent systemic therapy/RT, the preferred agent is cisplatin (category 1). vascular embolism, lymphatic invasion (See Discussion). See Principles of Systemic Therapy (CHEM-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Hypopharynx Discussion

RESPONSE ADJUVANT TREATMENT ASSESSMENT Primary site: Complete Definitive RTf response (category 1) (CR) and or stable or Consider systemic f,i Recurrent or improved therapy/RT See Follow-Up Recommendations Post persistent disease in (category 2B) Chemoradiation or RT (FOLL-A, 2 of 2) disease neck (See ADV-3)

Response Primary site: Systemic after Partial f,i induction response therapy/RT chemo- (PR) and (category 2B) therapyi,j stable or or No adverse for T2-3 improved RTg featuresh any N disease in g or T1, N+ neck Surgery Follow-up Extranodal Systemic therapy/RTf,i (See FOLL-A) extension and/or (category 1) positive margin Primary site: g Surgery Adverse < PR Recurrent featuresh RTf Other risk or or features persistent Consider systemic therapy/RTf,i disease (See ADV-3)

fSee Principles of Radiation Therapy (HYPO-A). gSee Principles of Surgery (SURG-A). iSee Principles of Systemic Therapy (CHEM-A). hAdverse features:extranodal extension, positive margins, pT3 or pT4 primary, N2 or N3 nodal jIn randomized clinical trials, assessment of response has disease, perineural invasion, vascular embolism, lymphatic invasion (See Discussion). been done after 2 or 3 cycles.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Hypopharynx Discussion

CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING Extranodal extension and/or f,i Total laryngopharyngectomy + Systemic therapy/RT (category 1) positive margin Follow-up neck dissection + hemi- or total (See FOLL-A) thyroidectomy, after ipsilateral RTf or bilateral paratracheal lymph Other risk or node dissectiong featuresh Consider systemic f,i Recurrent therapy/RT or persistent or disease Induction (See ADV-3) T4a, chemo- CT or MRI (with contrast) See Response Assessment (HYPO-6) any N therapyi,j of primary and neck (category 3)l

Concurrent systemic f,i,k See Follow-Up Recommendations Post therapy/RT Recurrent or persistent disease (See ADV-3) (category 3) Chemoradiation or RT (FOLL-A, 2 of 2)

Clinical trial

fSee Principles of Radiation Therapy (HYPO-A). gSee Principles of Surgery (SURG-A). jIn randomized clinical trials, assessment of response has been done hAdverse features: extranodal extension, positive margins, pT3 or pT4 primary, N2 or after 2 or 3 cycles. N3 nodal disease, perineural invasion, vascular embolism, lymphatic invasion (See kWhen using concurrent systemic therapy/RT, the preferred agent is Discussion). cisplatin (category 1). See Principles of Systemic Therapy (CHEM-A). iSee Principles of Systemic Therapy (CHEM-A). lSee Discussion on induction chemotherapy.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Hypopharynx Discussion

RESPONSE ASSESSMENT ADJUVANT TREATMENT

Primary RT site: CR and or stable or Consider improved Recurrent systemic or disease in f,i See Follow-Up Recommendations Post therapy/RT persistent neck Chemoradiation or RT (FOLL-A, 2 of 2) disease Response (See ADV-3) after Primary site: induction PR and stable Systemic chemo- or improved therapy/RTf,i therapyi,j disease in for T4a, neck any Nl No adverse RTf featuresh Primary site: Surgery Follow-up < PR or + neck Extranodal (See FOLL-A) g progression dissection extension and/or Systemic therapy/RTf,i (category 1) in neck as indicated positive margin Adverse Recurrent h or features RTf Other risk persistent or features disease Consider systemic therapy/RTf,i (See ADV-3)

fSee Principles of Radiation Therapy (HYPO-A). gSee Principles of Surgery (SURG-A). hAdverse features: extranodal extension, positive margins, pT3 iSee Principles of Systemic Therapy (CHEM-A). or pT4 primary, N2 or N3 nodal disease, perineural invasion, jIn randomized clinical trials, assessment of response has been done after 2 or 3 cycles. vascular embolism, lymphatic invasion (See Discussion). lSee Discussion on induction chemotherapy.

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. HYPO-6 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Hypopharynx Discussion

PRINCIPLES OF RADIATION THERAPY1,2 DEFINITIVE: RT Alone • PTV High risk: Primary tumor and involved lymph nodes (this includes possible local subclinical infiltration at the primary site and at the high-risk level lymph node(s)) ◊◊Fractionation: ––66 Gy (2.2 Gy/fraction) to 70 Gy (2.0 Gy/fraction); daily Monday–Friday in 6–7 weeks3 ––69.96 Gy (2.12 Gy/fraction) daily Monday–Friday in 6–7 weeks4 ––Concomitant boost accelerated RT: ▪▪72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) ▪▪66–70 Gy (2.0 Gy/fraction; 6 fractions/wk accelerated) ––Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)5

CONCURRENT CHEMORADIATION:6,7 • PTV High risk: typically 70 Gy (2.0 Gy/fraction) Low to intermediate risk: 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)5

Either IMRT or 3D conformal RT is recommended.

7Based on published data, concurrent chemoradiation most commonly uses conventional fractionation at 2.0 1See Radiation Techniques (RAD-A) and Discussion. Gy per fraction to a typical dose of 70 Gy in 7 weeks with single-agent cisplatin given every 3 weeks at 100 2Particular attention to speech and swallowing is needed during therapy. mg/m2; 2–3 cycles of chemotherapy are used depending on the radiation fractionation scheme (RTOG 0129) 3For doses >70 Gy, some clinicians feel that the fractionation should be (Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal slightly modified (eg, <2.0 Gy/fraction for at least some of the treatment) cancer. N Engl J Med 2010;363:24-35). When carboplatin and 5-FU are used, the recommended regimen to minimize toxicity. An additional 2–3 doses can be added depending is standard fractionation plus 3 cycles of chemotherapy. (Bourhis J, Sire C, Graff P, et al. Concomitant on clinical circumstances. chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally 4Eisbruch A, Harris J, Garden AS, et al. Multi-institutional trial of advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol accelerated hypofractionated intensity-modulated radiation therapy for 2012;13:145-153). Other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, other dosing early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol schedules of cisplatin, or altered fractionation with chemotherapy are efficacious, and there is no consensus Biol Phys 2010;76:1333-1338. on the optimal approach. In general, the use of concurrent chemoradiation carries a high toxicity burden; 5Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT altered fractionation or multiagent chemotherapy will likely further increase the toxicity burden. For any or 54–63 Gy with IMRT dose painting technique (dependent on dose chemoradiation approach, close attention should be paid to published reports for the specific chemotherapy per fraction). agent, dose, and schedule of administration. Chemoradiation should be performed by an experienced team 6See Principles of Systemic Therapy (CHEM-A). and should include substantial supportive care.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. HYPO-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Hypopharynx Discussion

PRINCIPLES OF RADIATION THERAPY1,2

POSTOPERATIVE: RT • Preferred interval between resection and postoperative RT is ≤6 weeks. • PTV High risk: Adverse features such as positive margins (See footnote h on HYPO-3). ◊◊60–66 Gy (2.0 Gy/fraction; daily Monday–Friday) in 6–6.5 weeks Low to intermediate risk: sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)5

POSTOPERATIVE CHEMORADIATION: • Concurrent systemic therapy6,8-11

Either IMRT or 3D conformal RT is recommended.

1See Radiation Techniques (RAD-A) and Discussion. 2Particular attention to speech and swallowing is needed during therapy. 5Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). 6See Principles of Systemic Therapy (CHEM-A). 8Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952. 9Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-1944. 10Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843-850. 11Cooper JS, Zhang Q, Pajak TF et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012;84:1198-1205.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. HYPO-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Nasopharynx Discussion

WORKUP CLINICAL STAGING

• H&Pa,b including a complete head and neck exam; mirror examination as clinically indicated • Nasopharyngeal fiberoptic examination See Treatment of Primary T1, N0, M0 • Biopsy of primary site or FNA of the neck and Neck (NASO-2) • MRI with contrast of skull base to clavicle ± CT of skull base/neck with contrast as clinically indicated to evaluate skull base erosion • Dental,c nutritional, speech and swallowing, and T1, N1-3; T2-T4, See Treatment of Primary audiology evaluations as clinically indicatedd Any N and Neck (NASO-2) • Imaging for distant metastases with FDG-PET/CT and/or chest CT with contrast • Consider Epstein-Barr virus (EBV)/DNA testinge • Consider ophthalmologic and endocrine evaluation as See Treatment of Primary Any T, Any N, M1 clinically indicated. and Neck (NASO-2)

Multidisciplinary consultation as clinically indicated

e aH&P should include documentation and quantification (pack years smoked) of tobacco For nonkeratinizing or undifferentiated histology, consider testing for EBV use history. Smoking cessation counseling as clinically indicated. All current smokers in tumor and blood. Common means for detecting EBV in pathologic should be advised to quit smoking, and former smokers should be advised to remain specimens include in situ hybridization for EBV-encoded RNA (EBER) or abstinent from smoking. For additional cessation support and resources, smokers can immunohistochemical staining for latent membrane protein (LMP). The EBV be referred to the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. DNA load within the serum or plasma may be quantified using polymerase bScreen for depression (See NCCN Guidelines for Distress Management). chain reaction (PCR) targeting genomic sequences of the EBV DNA such as cSee Principles of Dental Evaluation and Management (DENT-A). BamHI-W, EBNA, or LMP; these tests vary in their sensitivity. The EBV DNA dSee Principles of Nutrition: Management and Supportive Care (NUTR-A). load may reflect prognosis and change in response to therapy.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Nasopharynx Discussion

CLINICAL TREATMENT OF PRIMARY AND NECK FOLLOW-UP STAGING

Definitive RT to See Follow-Up Recommendations Post T1, N0, M0 nasopharynx and Chemoradiation or RT (FOLL-A, 2 of 2) elective RTf to neck

Clinical trials (preferred) or Concurrent chemo/RTf,g followed by adjuvant chemotherapyf T1, N1-3; or See Follow-Up Recommendations g,h T2-T4, any N Induction chemotherapy followed by Post Chemoradiation or RT f,g chemo/RT (FOLL-A, 2 of 2) or Concurrent chemo/RTf,g not followed by adjuvant chemotherapy (category 2B) Recurrent or persistent disease Clinical trials (preferred) (See ADV-3)

or RTf to primary and neck Platinum-based combination or g Follow-up (See FOLL-A) Any T, chemotherapy Chemo/RTf,g as any N, M1 or clinically indicated

Concurrent See Follow-Up Recommendations Post chemo/RTf,g,i Chemoradiation or RT (FOLL-A, 2 of 2)

fSee Principles of Radiation Therapy (NASO-A). gSee Principles of Systemic Therapy (CHEM-A). hSee Discussion on induction chemotherapy. iCan be used for select patients with distant metastasis in limited site or with small tumor burden, or for patients with symptoms in the primary or any nodal site.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Nasopharynx Discussion

PRINCIPLES OF RADIATION THERAPY1

DEFINITIVE: RT Alone (for T1, N0 or patients who are not eligible to receive chemotherapy) • PTV High risk: Primary tumor and involved lymph nodes (this includes possible local subclinical infiltration at the primary site and at the high-risk level lymph node(s)) ◊◊66 Gy (2.2 Gy/fraction) to 70–70.2 Gy (1.8–2.0 Gy/fraction); daily Monday–Friday in 6–7 weeks2,3 ◊◊69.96 Gy (2.12 Gy/fraction) daily Monday–Friday in 6–7 weeks4 • Low to intermediate risk: Sites of suspected subclinical spread 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)5

CONCURRENT CHEMORADIATION:6 (preferred for patients eligible for chemotherapy) • PTV High risk: typically 70–70.2 Gy (1.8–2.0 Gy/fraction); daily Monday–Friday in 7 weeks2 Low to intermediate risk: 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)5

Either IMRT (preferred) or 3D conformal RT is recommended for cancers of the nasopharynx to minimize dose to critical structures. Proton therapy can be considered when normal tissue constraints cannot be met by photon-based therapy.

1See Radiation Techniques (RAD-A) and Discussion. 2Care should be taken to avoid critical neural structures; therefore, 1.8 Gy/fraction can be considered. 3For doses >70 Gy, some clinicians feel that the fractionation should be slightly modified (eg, <2.0 Gy/fraction for at least some of the treatment) to minimize toxicity. An additional 2–3 doses can be added depending on clinical circumstances. 4Lee NY, Zhang Q, Pfister DG, et al. Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial. Lancet Oncol 2012;13:172-180. 5Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). 6See Principles of Systemic Therapy (CHEM-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Glottic Larynx Discussion

WORKUPa CLINICAL STAGING TREATMENT OF PRIMARY AND NECK Carcinoma in situ See Treatment (GLOT-2)

Amenable to larynx-preserving • H&Pb,c including a complete head and neck exam; (conservation) surgery See Treatment (GLOT-2) mirror and/or fiberoptic examination as clinically (T1-T2 or Select T3) indicated • Biopsy of primary site or FNA of the neck T3 requiring (amenable to) See Treatment of Primary and Neck • Chest CT (with or without contrast) as clinically total laryngectomy d (GLOT-3) indicated (N0-1) • CT with contrast and thin angled cuts through larynx and/or MRI with contrast of primary and neck • Consider FDG-PET/CT for stage III-IV disease T3 requiring (amenable to) See Treatment of Primary and Neck • EUA with endoscopy total laryngectomy (GLOT-4) • Preanesthesia studies (N2-3) • Dental evaluation as clinically indicatede • Nutrition, speech and swallowing evaluation/ See Treatment of Primary and Neck therapy, and audiogram as clinically indicatedf T4a disease (GLOT-6) • Consider videostrobe for select patients • Pulmonary function evaluation for conservation T4b, any N surgery candidates or Unresectable nodal disease See Treatment of Very Advanced Head and Neck Cancer (ADV-1) Multidisciplinary consultation as clinically indicated or Unfit for surgery

Metastatic (M1) disease See Treatment of Very Advanced at initial presentation Head and Neck Cancer (ADV-2) aComplete workup may not be indicated for Tis, T1, but history and physical examination and biopsy are required. Direct laryngoscopy under anesthesia is generally recommended for all cases. cScreen for depression (See NCCN Guidelines for Distress Management). bH&P should include documentation and quantification (pack years smoked) of tobacco dChest CT is recommended for advanced nodal disease to screen for use history. Smoking cessation counseling as clinically indicated. All current smokers distant metastases, and for select patients who smoke to screen for lung should be advised to quit smoking, and former smokers should be advised to remain cancer. See NCCN Guidelines for Lung Cancer Screening. abstinent from smoking. For additional cessation support and resources, smokers can eSee Principles of Dental Evaluation and Management (DENT-A). be referred to the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. fSee Principles of Nutrition: Management and Supportive Care (NUTR-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Glottic Larynx Discussion

CLINICAL STAGING TREATMENT OF PRIMARY AND NECK ADJUVANT FOLLOW-UP TREATMENT

Endoscopic resection (preferred) Carcinoma in situ or RTg

RTg

Amenable to larynx- or i preserving No adverse features Observation (conservation) Recurrent surgery (T1-T2 or Partial laryngectomy/ or Follow-up select T3) endoscopic or open Extranodal Chemo/RTg,j persistent h (See FOLL-A) resection as indicated extension (category 1) disease and neck dissection as (See ADV-3) indicated Re-resection, Adverse Positive if feasible featuresi margin or RTg

Other risk RTg features

gSee Principles of Radiation Therapy (GLOT-A). hSee Principles of Surgery (SURG-A). iAdverse features: extranodal extension, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease, perineural invasion, vascular embolism, lymphatic invasion (See Discussion). jSee Principles of Systemic Therapy (CHEM-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Glottic Larynx Discussion

CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING Concurrent systemic therapy/RTg,j,k Recurrent or See Follow-Up Recommendations Post or RTg if patient Chemoradiation or RT (FOLL-A, 2 of 2) persistent not candidate disease for systemic (See ADV-3) therapy/RT Laryngectomy with ipsilateral T3 requiring or thyroidectomy, pretracheal (amenable N0 No adverse Follow-up and ipsilateral paratracheal i to) total features (See FOLL-A) lymph node dissectionh Extranodal laryngectomy h Systemic Surgery extension and/ (N0-1) Laryngectomy with ipsilateral therapy/RTg,j or positive thyroidectomy as indicated, (category 1) Recurrent N1 Adverse margin ipsilateral neck dissection, or featuresi RTg or bilateral neck dissection, persistent and pretracheal and ipsilateral or Other risk disease paratracheal lymph node Consider or features (See ADV-3) dissectionh systemic therapy/RTg,j

Induction chemotherapy CT or MRI (with contrast) j,l See Response Assessment (GLOT-5) (category 2B) of primary and neck or

Clinical trials

gSee Principles of Radiation Therapy (GLOT-A). jSee Principles of Systemic Therapy (CHEM-A). hSee Principles of Surgery (SURG-A). kWhen using concurrent systemic therapy/RT, the preferred agent is iAdverse features: extranodal extension, positive margins, pT4 primary, N2 or N3 nodal cisplatin (category 1). disease, perineural invasion, vascular embolism, lymphatic invasion (See Discussion). lSee Discussion on induction chemotherapy.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Glottic Larynx Discussion

CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING

Concurrent systemic See Follow-Up Recommendations Post Recurrent or persistent therapy/RTg,j,k Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3)

or No adverse Laryngectomy with i thyroidectomy, ipsilateral features Extranodal or bilateral neck Systemic Surgeryh extension and/ T3 requiring dissection, and pretracheal therapy/RTg,j or positive Follow-up (amenable to) and ipsilateral paratracheal (category 1) Adverse margin (See FOLL-A) total lymph node dissectionh featuresi laryngectomy RTg or (N2-3) Other risk Consider features systemic Recurrent or g,j therapy/RT or persistent Induction CT or MRI (with contrast) See Response Assessment (GLOT-5) disease chemotherapyj,l of primary and neck (See ADV-3) or Clinical trials

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. GLOT-4 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Glottic Larynx Discussion

RESPONSE ASSESSMENT

Primary site: Definitive RTg CR (category 1)

Recurrent or See Follow-Up Recommendations Post persistent disease RTg Chemoradiation or RT (FOLL-A, 2 of 2) Response (See ADV-3) (category 1) after Primary site: or induction PR Systemic chemotherapy/RTg,j therapyj,m (category 2B)

No adverse RTg featuresi Follow-up (See FOLL-A) Extranodal Primary site: Laryngectomyh Systemic therapy/RTg,j extension and/or < PR (category 1) positive margin Recurrent Adverse or g featuresi RT persistent Other risk or disease features Consider systemic (See ADV-3) therapy/RTg,j

gSee Principles of Radiation Therapy (GLOT-A). hSee Principles of Surgery (SURG-A). jSee Principles of Systemic Therapy (CHEM-A). iAdverse features: extranodal extension, positive margins, pT3 or pT4 primary, N2 or N3 mIn randomized clinical trials, assessment of response has been nodal disease, perineural invasion, vascular embolism, lymphatic invasion (See Discussion). done after 2 or 3 cycles.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Glottic Larynx Discussion

CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING Total laryngectomy with thyroidectomy ± unilateral or bilateral N0 neck dissection, and pretracheal and ipsilateral paratracheal lymph node No adverse dissectionh featuresi Extranodal Follow-up Systemic Total laryngectomy with thyroidectomy, extension and/ (See FOLL-A) therapy/RTg,j ipsilateral neck dissection or positive h (category 1) T4a, Any N Surgery N1 ± contralateral neck dissection, and margin pretracheal and ipsilateral paratracheal lymph node dissectionh Adverse RTg featuresi Recurrent or Total laryngectomy with Other risk Consider systemic or thyroidectomy, ipsilateral or bilateral features therapy/RTg,j persistent N2-3 neck dissection, and pretracheal and or disease ipsilateral paratracheal lymph node Observation for (See ADV-3) h dissection highly selected patientsn

See Follow-Up Recommendations Post Recurrent or persistent Consider concurrent systemic therapy/RTg,j Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3) Selected T4a or patients who Clinical trial for function-preserving decline surgical or nonsurgical management surgery or CT or MRI (with contrast) Induction chemotherapyj,l See Response Assessment (GLOT-5) of primary and neck gSee Principles of Radiation Therapy (GLOT-A). nGood-risk features for favorable T4a patients who could be observed after surgery include: hSee Principles of Surgery (SURG-A). • Indolent histopathology: papillary variant of squamous cell carcinoma, verrucous carcinoma. iAdverse features: extranodal extension, positive margins, pT3 or • Widely negative margins, pN0 neck, especially central compartment (Level VI) without pT4 primary, N2 or N3 nodal disease, perineural invasion, vascular perineural invasion, or lymphovascular invasion. embolism, lymphatic invasion (See Discussion). • Low-volume disease with microscopic extralaryngeal extension beyond the laryngeal jSee Principles of Systemic Therapy (CHEM-A). skeleton and widely negative margins. lSee Discussion on induction chemotherapy. • pN0, Broders’ grade I-II, subglottic extension <1 cm.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Glottic Larynx Discussion

PRINCIPLES OF RADIATION THERAPY1 DEFINITIVE: CONCURRENT CHEMORADIATION:4,5 RT Alone • PTV • Tis, N0: 60.75 Gy (2.25 Gy/fraction) to 66 Gy (2.0 Gy/fraction) High risk: typically 70 Gy (2.0 Gy/fraction) • T1, N0: 63 Gy (2.25 Gy/fraction) to 66 Gy (2.0 Gy/fraction) Low to intermediate risk: 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy • T2, N0: 65.25 (2.25 Gy/fraction) to 70 Gy (2.0 Gy/fraction) (1.6–1.8 Gy/fraction)3 • ≥ T2, N1: PTV ◊◊High risk: Primary tumor and involved lymph nodes (this includes possible local subclinical infiltration at the primary site and at the high-risk level lymph node(s)) ––Fractionation: 66 Gy (2.2 Gy/fraction) to 70 Gy (2.0 Gy/ fraction); daily Monday–Friday in 6–7 weeks2 ––Concomitant boost accelerated RT: ▪▪72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) ▪▪66–70 Gy (2.0 Gy/fraction; 6 fractions/wk accelerated) ––Hyperfractionation: 79.2–81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) ◊◊Low to intermediate risk: Sites of suspected subclinical spread ––44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)3

Either IMRT or 3D conformal RT is recommended.

1See Radiation Techniques (RAD-A) and Discussion. the recommended regimen is standard fractionation plus 3 cycles of chemotherapy. 2For doses >70 Gy, some clinicians feel that the fractionation should be slightly modified (Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration (eg, <2.0 Gy/fraction for at least some of the treatment) to minimize toxicity. An of radiotherapy with or without concomitant chemotherapy in locally advanced head additional 2–3 doses can be added depending on clinical circumstances. and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet 3Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy Oncol 2012;13:145-153). Other fraction sizes (eg, 1.8 Gy, conventional), multiagent with IMRT dose painting technique (dependent on dose per fraction). chemotherapy, other dosing schedules of cisplatin, or altered fractionation with 4See Principles of Systemic Therapy (CHEM-A). chemotherapy are efficacious, and there is no consensus on the optimal approach. 5Based on published data, concurrent chemoradiation most commonly uses conventional In general, the use of concurrent chemoradiation carries a high toxicity burden; fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with single- altered fractionation or multiagent chemotherapy will likely further increase the toxicity agent cisplatin given every 3 weeks at 100 mg/m2 ; 2–3 cycles of chemotherapy are burden. For any chemoradiation approach, close attention should be paid to published used depending on the radiation fractionation scheme (RTOG 0129) (Ang KK, Harris reports for the specific chemotherapy agent, dose, and schedule of administration. J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal Chemoradiation should be performed by an experienced team and should include cancer. N Engl J Med 2010;363:24-35). When carboplatin and 5-FU are used, then substantial supportive care.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. GLOT-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Glottic Larynx Discussion

PRINCIPLES OF RADIATION THERAPY1

POSTOPERATIVE: RT • Preferred interval between resection and postoperative RT is ≤6 weeks. • PTV High risk: Adverse features such as positive margins (See footnote i on GLOT-3). ◊◊60–66 Gy (2.0 Gy/fraction); daily Monday–Friday in 6–6.5 weeks Low to intermediate risk: sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)3

POSTOPERATIVE CHEMORADIATION: • Concurrent systemic therapy4,6-9

Either IMRT or 3D conformal RT is recommended.

1See Radiation Techniques (RAD-A) and Discussion. 3Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). 4See Principles of Systemic Therapy (CHEM-A). 6Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952. 7Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-1944. 8Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843-850. 9Cooper JS, Zhang Q, Pajak TF et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012;84:1198-1205.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. GLOT-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Supraglottic Larynx Discussion

WORKUP CLINICAL STAGING Amenable to larynx-preserving See Treatment of Primary (conservation) surgery and Neck (SUPRA-2) (Most T1-2, N0; Selected T3)

• H&Pa,b including a complete head and neck exam; mirror and/or fiberoptic examination as Requiring (amenable to) total See Treatment of Primary clinically indicated laryngectomy (T3, N0) and Neck (SUPRA-3) • Biopsy of primary site or FNA of the neck • Chest CT (with or without contrast) as c clinically indicated See Treatment of Primary T4a, N0 • CT with contrast and thin angled cuts through and Neck (SUPRA-8) larynx and/or MRI of primary and neck • Consider FDG-PET/CT for stage III-IV disease • EUA with endoscopy • Preanesthesia studies See Clinical Staging d Node-positive disease • Dental evaluation as clinically indicated (SUPRA-4) • Nutrition, speech and swallowing evaluation/ therapy, and audiogram as clinically indicatede T4b, any N • Consider videostrobe for select patients or See Treatment of Very • Consider pulmonary function tests for Unresectable nodal disease Advanced Head and Neck conservation surgery candidates or Cancer (ADV-1) Unfit for surgery Multidisciplinary consultation as indicated See Treatment of Very Metastatic (M1) disease Advanced Head and Neck at initial presentation Cancer (ADV-2)

aH&P should include documentation and quantification (pack years smoked) of tobacco use history. Smoking cessation counseling as clinically indicated. All current smokers cChest CT is recommended for advanced nodal disease to screen for distant should be advised to quit smoking, and former smokers should be advised to remain metastases, and for select patients who smoke to screen for lung cancer. See abstinent from smoking. For additional cessation support and resources, smokers can NCCN Guidelines for Lung Cancer Screening. be referred to the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. dSee Principles of Dental Evaluation and Management (DENT-A). bScreen for depression (See NCCN Guidelines for Distress Management). eSee Principles of Nutrition: Management and Supportive Care (NUTR-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Supraglottic Larynx Discussion

CLINICAL STAGING TREATMENT OF PATHOLOGY ADJUVANT FOLLOW-UP PRIMARY AND NECK STAGE TREATMENT Node negative (T1-T2, N0)

One positive node without other Consider RTg h adverse features Re-resection, if feasible in highly selected patients Positive node; or g Endoscopic resection positive margin RT Recurrent + neck dissectionf or or Follow-up Amenable to or Consider systemic persistent g,i (See FOLL-A) larynx-preserving Open partial therapy/RT disease (conservation) surgery supraglottic Systemic therapy/ (See ADV-3) (Most T1-2, N0; laryngectomy + neck RTg,i (category 1) Selected T3 patients) dissectionf Extranodal extension or g or RT (category 2B, Definitive RTg for select patients) RTg Positive node; or Other adverse h Consider systemic risk features therapy/RTg,i

Node negative, See Treatment (T3-T4a, N0) (SUPRA-3) and (SUPRA-8)

See Follow-Up Recommendations Post Chemoradiation or RT (FOLL-A, 2 of 2)

fSee Principles of Surgery (SURG-A). gSee Principles of Radiation Therapy (SUPRA-A). hAdverse features: extranodal extension, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease, perineural invasion, vascular embolism, lymphatic invasion (See Discussion. iSee Principles of Systemic Therapy (CHEM-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Supraglottic Larynx Discussion

CLINICAL STAGING TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT

Concurrent systemic therapy/RTg,i,j Recurrent or or See Follow-Up Recommendations Post g persistent disease RT if patient not Chemoradiation or RT (FOLL-A, 2 of 2) medical candidate for (See ADV-3) concurrent systemic therapy/RT

or N0 or one positive node Consider RTg without adverse featuresh Laryngectomy, thyroidectomy and with ipsilateral, Extranodal Systemic g,i central, or bilateral extension and/or therapy/RT Follow-up neck dissectionf positive margin (category 1) (See FOLL-A) Requiring Adverse (amenable to) total h g features RT Recurrent laryngectomy or Other risk or (T3, N0) Consider or features persistent systemic g,i disease therapy/RT (See ADV-3) Induction CT or MRI (with contrast) See Response Assessment (SUPRA-7) chemotherapyi,k of primary and neck

Clinical trials

fSee Principles of Surgery (SURG-A). gSee Principles of Radiation Therapy (SUPRA-A). hAdverse features: extranodal extension, positive margins, pT3 or pT4 primary, N2 or N3 jWhen using concurrent systemic therapy/RT, the preferred agent is nodal disease, perineural invasion, vascular embolism, lymphatic invasion (See Discussion). cisplatin (category 1). See Principles of Systemic Therapy (CHEM-A). iSee Principles of Systemic Therapy (CHEM-A). kSee Discussion on induction chemotherapy.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Supraglottic Larynx Discussion

CLINICAL STAGING

Amenable to larynx-preserving (conservation) surgery See Treatment of Primary and Neck (SUPRA-5) (T1-2, N+ and selected T3, N1)

Requiring (amenable to) total See Treatment of Primary and Neck (SUPRA-6) laryngectomy (Most T3, N2-3)

Node-positive disease

T4a, N1-N3 See Treatment of Primary and Neck (SUPRA-8)

T4b, any N or Unresectable nodal disease See Treatment of Head and Neck Cancer (ADV-1) or Unfit for surgery

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Supraglottic Larynx Discussion

CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT STAGING Concurrent systemic therapy/RTg,i,j Recurrent or See Follow-Up Recommendations Post persistent disease or Chemoradiation or RT (FOLL-A, 2 of 2) (See ADV-3) Definitive RTg

or No adverse Observation Amenable to featuresh or RTg larynx- preserving Partial supraglottic Extranodal extension and/or Systemic therapy/RTg,i Follow-up (conservation) laryngectomy and l surgery neck dissection(s)f positive margin (category 1) (See FOLL-A) (T1-2, N+ and Adverse h RTg selected features Other risk or T3, N1) Recurrent features Consider systemic therapy/RTg,i or or persistent disease Induction CT or MRI (with contrast) See Response Assessment (SUPRA-7) (See ADV-3) chemotherapyi,k of primary and neck

Clinical trials

fSee Principles of Surgery (SURG-A). jWhen using concurrent systemic therapy/RT, the preferred agent is cisplatin gSee Principles of Radiation Therapy (SUPRA-A). (category 1). See Principles of Systemic Therapy (CHEM-A). hAdverse features: extranodal extension, positive margins, pT3 or pT4 primary, kSee Discussion on induction chemotherapy. N2 or N3 nodal disease, perineural invasion, vascular embolism, lymphatic lIn highly select patients, re-resection (if negative margins are feasible and can invasion (See Discussion). be achieved without total laryngectomy) where it would potentially change the iSee Principles of Systemic Therapy (CHEM-A). subsequent indication for chemotherapy.

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. SUPRA-5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Supraglottic Larynx Discussion

CLINICAL STAGING TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT

Recurrent or Concurrent systemic See Follow-Up Recommendations Post persistent g,i,j therapy/RT Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3) or No adverse RTg featuresh Laryngectomy, Requiring ipsilateral Extranodal Follow-up extension and/ (amenable to) total thyroidectomy Systemic therapy/RTg,i (category 1) (See FOLL-A) laryngectomy with neck or positive (Most T3, N2-N3) dissectionf margin Adverse h RTg Recurrent features Other risk or or or features Consider systemic therapy/RTg,i persistent disease (See ADV-3) Induction CT or MRI (with contrast) See Response Assessment (SUPRA-7) chemotherapyi,k of primary and neck or Clinical trials

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. SUPRA-6 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Supraglottic Larynx Discussion

RESPONSE ASSESSMENT

Primary site: Definitive RTg CR (category 1)

Recurrent or See Follow-Up Recommendations Post persistent Chemoradiation or RT (FOLL-A, 2 of 2) disease RTg Response after (See ADV-3) (category 1) induction Primary site: or systemic chemo- PR therapy/RTg,i therapyi,m (category 2B)

No adverse RTg featuresh

Primary site: Surgeryf Extranodal < PR Systemic therapy/RTg,i Follow-up extension and/or (category 1) (See FOLL-A) Adverse positive margin featuresh RTg Other risk or Recurrent features Consider systemic therapy/RTg,i or persistent disease fSee Principles of Surgery (SURG-A). (See ADV-3) gSee Principles of Radiation Therapy (SUPRA-A). hAdverse features: extranodal extension, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease, perineural invasion, vascular embolism, lymphatic invasion (See Discussion). iSee Principles of Systemic Therapy (CHEM-A). mIn randomized clinical trials, assessment of response has been done after 2 or 3 cycles.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Supraglottic Larynx Discussion

CLINICAL TREATMENT OF PRIMARY AND NECK ADJUVANT STAGING TREATMENT

Extranodal Follow-up Systemic therapy/RTg,i extension and/or (See FOLL-A) h (category 1) Laryngectomy, thyroidectomy positive margin T4a, N0-N3 as indicated with ipsilateral or RTg bilateral neck dissectionf Other risk or featuresh Consider systemic Recurrent therapy/RTg,i or persistent disease (See ADV-3)

Consider concurrent See Follow-Up Recommendations Post Recurrent or persistent systemic therapy/RTg,i Chemoradiation or RT (FOLL-A, 2 of 2) disease (See ADV-3)

or T4a, N0-N3 patients who Clinical trial decline surgery or

i,k CT or MRI (with contrast) Induction chemotherapy of primary and neck See Response Assessment (SUPRA-7)

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Supraglottic Larynx Discussion

PRINCIPLES OF RADIATION THERAPY1 DEFINITIVE: CONCURRENT CHEMORADIATION:5,6 RT Alone • PTV • T1-2, N0: 66–70 Gy conventional (2.0 Gy/fraction)2 High risk: typically 70 Gy (2.0 Gy/fraction) • T2-3, N0-1: Low to intermediate and low risk: 44–50 Gy (2.0 Gy/fraction) to PTV 54–63 Gy (1.6–1.8 Gy/fraction)4 ◊◊High risk: Primary tumor and involved lymph nodes (this includes possible local subclinical infiltration at the primary site and at the high-risk level lymph node(s)) ––Fractionation: 66 Gy (2.2 Gy/fraction) to 70 Gy (2.0 Gy/ fraction); daily Monday–Friday in 6–7 weeks3 ––Concomitant boost accelerated RT: ▪▪72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) ▪▪66–70 Gy (2.0 Gy/fraction; 6 fractions/wk accelerated) ––Hyperfractionation: 79.2–81.6 Gy/7 weeks (1.2 Gy/fraction twice daily) ◊◊Low to intermediate risk: Sites of suspected subclinical spread ––44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4

Either IMRT or 3D conformal RT is recommended.

1See Radiation Techniques (RAD-A) and Discussion. 2For select T1-2, N0 tumors, accelerated fractionation may be used. 3For doses >70 Gy, some clinicians feel that the fractionation should be slightly modified (eg, <2.0 Gy/fraction for at least some of the treatment) to minimize toxicity. An additional 2–3 doses can be added depending on clinical circumstances. 4Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). 5See Principles of Systemic Therapy (CHEM-A). 6Based on published data, concurrent chemoradiation most commonly uses conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with single- agent cisplatin given every 3 weeks at 100 mg/m2; 2–3 cycles of chemotherapy are used depending on the radiation fractionation scheme (RTOG) (Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24-35). When carboplatin and 5-FU are used, the recommended regimen is standard fractionation plus 3 cycles of chemotherapy. (Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol 2012;13:145-153). Other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, other dosing schedules of cisplatin, or altered fractionation with chemotherapy are efficacious, and there is no consensus on the optimal approach. In general, the use of concurrent chemoradiation carries a high toxicity burden; altered fractionation or multiagent chemotherapy will likely further increase the toxicity burden. For any chemoradiation approach, close attention should be paid to published reports for the specific chemotherapy agent, dose, and schedule of administration. Chemoradiation should be performed by an experienced team and should include substantial supportive care.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SUPRA-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Cancer of the Supraglottic Larynx Discussion

PRINCIPLES OF RADIATION THERAPY1

POSTOPERATIVE: RT • Preferred interval between resection and postoperative RT is ≤6 weeks. • PTV High risk: Adverse features such as positive margins (See footnote h on SUPRA-3). ◊◊60–66 Gy (2.0 Gy/fraction); daily Monday–Friday in 6–6.5 weeks Low to intermediate risk: sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4

POSTOPERATIVE CHEMORADIATION: • Concurrent systemic therapy5,7-10

Either IMRT or 3D conformal RT is recommended.

1See Radiation Techniques (RAD-A) and Discussion. 4Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). 5See Principles of Systemic Therapy (CHEM-A). 7Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952. 8Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-1944. 9Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843-850. 10Cooper JS, Zhang Q, Pajak TF et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012;84:1198-1205.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SUPRA-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Ethmoid Sinus Tumors Discussion

WORKUP PATHOLOGY

• Squamous cell carcinoma • Adenocarcinoma • Minor salivary gland tumore See Primary • Esthesioneuroblastoma Treatment • Undifferentiated carcinoma (sinonasal (ETHM-2) undifferentiated carcinoma [SNUC], small cell, or sinonasal f • H&Pa,b including a complete head and neuroendocrine carcinoma [SNEC]) neck exam; nasal endoscopy as clinically indicated • CT with contrast or MRI with contrast of Mucosal melanoma Biopsy skull base (See NCCN Guidelines for Mucosal Melanoma MM-1) • Dental consultationc as clinically indicated • Chest CT (with or without contrast) as d clinically indicated Sarcoma • Consider FDG-PET/CT for stage III or IV (See NCCN Guidelines for Soft Tissue Sarcoma)

Multidisciplinary consultation as indicated

Lymphoma (See NCCN Guidelines for Non-Hodgkin's Lymphomas)

aH&P should include documentation and quantification (pack years smoked) of tobacco use history. Smoking cessation counseling as clinically indicated. All current smokers dChest CT is recommended for advanced nodal disease to screen for distant should be advised to quit smoking, and former smokers should be advised to remain metastases. abstinent from smoking. For additional cessation support and resources, smokers can eAlso see the NCCN Guidelines for Salivary Gland Tumors (SALI-1). be referred to the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. fFor SNUC, small cell, or SNEC histologies, systemic therapy should be a bScreen for depression (See NCCN Guidelines for Distress Management). part of the overall treatment. Consider a clinical trial and referral to a major cSee Principles of Dental Evaluation and Management (DENT-A). medical center that specializes in these diseases.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Ethmoid Sinus Tumors Discussion

CLINICAL PRIMARY TREATMENTf ADJUVANT TREATMENTf FOLLOW-UP PRESENTATION RTi or Observek for T1 only (category 2B) Surgical resectiong,h (preferred) Follow-up or i,j (See FOLL-A) or Consider systemic therapy/RT Newly diagnosed T1, T2 (category 2B) if adverse featuresl See Follow-Up Recommendations Post Definitive RTi Recurrent Chemoradiation or RT (FOLL-A, 2 of 2) or RTi persistent or disease Surgical resectiong,h (preferred) Consider systemic therapy/RTi,j (See ADV-3) Newly diagnosed T3, T4a or (category 2B) if adverse featuresl Systemic therapy/RTi,j See Follow-Up Recommendations Post Systemic therapy/RTi,j Chemoradiation or RT (FOLL-A, 2 of 2) or Newly diagnosed T4b or RTi patient declines surgery or Clinical trial (preferred) Diagnosed after Gross residual incomplete disease resection (eg, No residual disease See Primary Treatment (ETHM-3) polypectomy) on physical exam, imaging, and/or endoscopy

Metastatic disease at initial presentation See Treatment of Very Advanced Head and Neck Cancer (ADV-2)

hSee Principles of Surgery (SURG-A). fFor SNUC, small cell, or SNEC histologies, systemic therapy should iSee Principles of Radiation Therapy (ETHM-A). For minor salivary gland tumors, see SALI-A. be a part of the overall treatment. Consider a clinical trial and referral jSee Principles of Systemic Therapy (CHEM-A). to a major medical center that specializes in these diseases. kPathologic features: negative margins, central tumors, and low-grade tumors. gN+ neck disease is uncommon in ethmoid cancers, but, if present, lAdverse features include positive margins, high-grade lesions, and intracranial extension requires neck dissection and appropriate risk-based adjuvant therapy. (See Discussion).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Ethmoid Sinus Tumors Discussion

CLINICAL PRIMARY TREATMENTf ADJUVANT TREATMENTf FOLLOW-UP PRESENTATION

RTf,i or Surgeryh (preferred), if feasible Consider systemic therapy/RTi,j Diagnosed after incomplete or (category 2B) if adverse featuresl resection (eg, polypectomy) RTi Follow-up and gross residual disease or (See FOLL-A) Systemic therapy/RTi,j

Recurrent i or Diagnosed after incomplete RT persistent resection (eg, polypectomy) and i RT disease no residual disease on physical or or (See ADV-3) exam, imaging, and/or endoscopy Observek for T1 only (category Surgery,h if feasible 2B) or Consider systemic therapy/RTi,j (category 2B) if adverse featuresl

fFor SNUC, small cell, or SNEC histologies, systemic therapy should be a part of the overall treatment. Consider a clinical trial and referral to a major medical center that specializes in these diseases. hSee Principles of Surgery (SURG-A). iSee Principles of Radiation Therapy (ETHM-A). For minor salivary gland tumors, see SALI-A. jSee Principles of Systemic Therapy (CHEM-A). kPathologic features: negative margins, favorable histology, central tumors, and low-grade tumors. lAdverse features include positive margins, high-grade lesions, and intracranial extension (See Discussion).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Ethmoid Sinus Tumors Discussion

PRINCIPLES OF RADIATION THERAPY1

DEFINITIVE: POSTOPERATIVE: RT Alone RT • PTV • Preferred interval between resection and postoperative RT is ≤6 weeks High risk: Primary tumor and involved lymph nodes (this includes • PTV possible local subclinical infiltration at the primary site and at the High risk: Adverse features such as positive margins high-risk level lymph node(s)) (See footnote l on ETHM-2) ◊◊Fractionation: ◊◊60–66 Gy (1.8–2.0 Gy/fraction); daily Monday–Friday in 6–6.5 ––66 Gy (2.2 Gy/fraction) to 70–70.2 Gy (1.8–2.0 Gy/fraction); weeks2 daily Monday-Friday in 6–7 weeks2,3 Low to intermediate risk: sites of suspected subclinical spread ––Concomitant boost accelerated RT: ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4,5 ▪▪72 Gy/6 weeks (2 Gy once daily and then 1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last POSTOPERATIVE CHEMORADIATION 6 12 treatment days) • Concurrent systemic therapy ▪▪66–70 Gy (2.0 Gy/fraction; 6 fractions/wk accelerated) ––Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4,5 CONCURRENT CHEMORADIATION:6 • PTV Either IMRT(preferred) or 3D conformal RT is recommended for High risk: typically 70–70.2 Gy (1.8–2.0 Gy/fraction); daily maxillary sinus or paranasal/ethmoid sinus tumors to minimize Monday–Friday in 7 weeks2 dose to critical structures. Proton therapy can be considered when Low to intermediate risk: 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy normal tissue constraints cannot be met by photon-based therapy. (1.6–1.8 Gy/fraction)4,5

1See Radiation Techniques (RAD-A) and Discussion. 2In the paranasal sinus area, care should be taken to avoid critical neural structures; therefore, 1.8 Gy/fraction can be considered. 3For doses >70 Gy, some clinicians feel that the fractionation should be slightly modified (eg, <2.0 Gy/fraction for at least some of the treatment) to minimize toxicity. An additional 2–3 doses can be added depending on clinical circumstances. 4Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). 5Treatment to sites of suspected subclinical spread is not consistently performed at all institutions. (Le QT, Fu KK, Kaplan MJ, et al. Lymph node metastasis in maxillary sinus carcinoma. Int J Radiat Oncol Biol Phys 2000;46:541-549.) 6See Principles of Systemic Therapy (CHEM-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Maxillary Sinus Tumors Discussion

WORKUP PATHOLOGY • Squamous cell carcinoma T1-2, N0 See Primary • Adenocarcinoma All histologies Treatment (MAXI-2) • Minor salivary gland tumorf • Esthesioneuroblastoma • Undifferentiated carcinoma (sinonasal undifferentiated a,b T3-4, N0, Any T, N+ See Primary • H&P including a carcinoma [SNUC], small cell, All histologies Treatment (MAXI-3) complete head and neck or sinonasal neuroendocrine exam; nasal endoscopy carcinoma [SNEC])g as clinically indicated • Complete head and neck CT with contrast and/or Mucosal melanoma MRI with contrast (See NCCN Guidelines for Mucosal Melanoma MM-1) • Dentalc/prosthetic Biopsye consultation as clinically indicated • Chest CT (with or Sarcoma without contrast) as (See NCCN Guidelines for Soft Tissue Sarcoma) clinically indicatedd • Consider FDG-PET/CT for Stage III or IV Lymphoma (See NCCN Guidelines for Non-Hodgkin's Lymphomas) Multidisciplinary consultation as indicated

aH&P should include documentation and quantification (pack years smoked) of tobacco use history. Smoking cessation counseling as clinically indicated. All current smokers eBiopsy: should be advised to quit smoking, and former smokers should be advised to remain • Preferred route is transnasal. abstinent from smoking. For additional cessation support and resources, smokers can • Needle biopsy may be acceptable. be referred to the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. • Avoid canine fossa puncture or Caldwell-Luc approach. bScreen for depression (See NCCN Guidelines for Distress Management). fAlso see the NCCN Guidelines for Salivary Gland Tumors (SALI-1). cSee Principles of Dental Evaluation and Management (DENT-A). gFor SNUC, small cell, or SNEC histologies, systemic therapy should dChest CT is recommended for advanced nodal disease to screen for distant be a part of the overall treatment. Consider a clinical trial and metastases. referral to a major medical center that specializes in these diseases.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Maxillary Sinus Tumors Discussion

STAGING PRIMARY TREATMENTg ADJUVANT TREATMENTg FOLLOW-UP

Margin negative

T1-2, N0 Perineural, Consider RTi All histologies Surgical vascular, or or except resectionh lymphatic Consider systemic therapy/RTi,j (category 2B) adenoid cystic invasion Margin Consider RTi negative Recurrent Margin Re-resection, h or RT Follow-up positive if feasible Persistent or (See FOLL-A) Margin Consider Disease positive systemic (See ADV-3) therapy/RTi,j (category 2B) Suprastructureh RTi,k T1-2, N0 Surgical Adenoid resectionh Consider observation cystic for margin negative, no Infrastructureh perineural spread or RTi,k

gFor SNUC, small cell, or SNEC histologies, systemic therapy should be a part of the overall treatment. Consider a clinical trial and referral to a major medical center that specializes in these diseases. hSee Principles of Surgery (SURG-A). iSee Principles of Radiation Therapy (MAXI-A). jSee Principles of Systemic Therapy (CHEM-A). kFor adenoid cystic tumors and minor salivary gland tumors, see SALI-A.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Maxillary Sinus Tumors Discussion

STAGING PRIMARY TREATMENTg ADJUVANT TREATMENTg FOLLOW-UP RTi or Adverse l Consider systemic Recurrent features i,j therapy/RT (category or Complete Follow-up 2B) to primary and neck Persistent T3-T4a, N0 surgical (See FOLL-A) Disease resectiong (See ADV-3) RTi,k to primary and neck (category 2B No adverse for neck for squamous cell carcinoma featuresl and undifferentiated tumors) Clinical trial or Definitive RTi,k T4b, any N or See Follow-Up Recommendations Post Recurrent or persistent disease Systemic Chemoradiation or RT (FOLL-A, 2 of 2) (See ADV-3) therapy/RTi,j RTi,k Adverse or featuresl Consider systemic therapy/RTi,j Recurrent Surgical or to primary and neck (category 2B) Follow-up resection Persistent T1-T4a, N+ (See FOLL-A) + neck Disease h dissection No adverse (See ADV-3) RTi,k to primary + neck featuresl

Metastatic disease at initial presentation See Treatment of Very Advanced Head and Neck Cancer (ADV-2)

gFor SNUC, small cell, or SNEC histologies, systemic therapy should be a part of the overall treatment. Consider a clinical trial and referral to a major medical center that specializes in these diseases. jSee Principles of Systemic Therapy (CHEM-A). hSee Principles of Surgery (SURG-A). kFor adenoid cystic tumors and minor salivary gland tumors, see SALI-A. iSee Principles of Radiation Therapy (MAXI-A). lAdverse features include positive margins or extranodal extension (See Discussion).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Maxillary Sinus Tumors Discussion

PRINCIPLES OF RADIATION THERAPY1

DEFINITIVE: POSTOPERATIVE: RT Alone RT • PTV • Preferred interval between resection and postoperative RT is ≤6 High risk: Primary tumor and involved lymph nodes (this includes weeks possible local subclinical infiltration at the primary site and at the • PTV high-risk level lymph node(s)) High risk: Adverse features such as positive margins (See ◊◊Fractionation: footnote l on MAXI-3) ––66 Gy (2.2 Gy/fraction) to 70–70.2 Gy (1.8–2.0 Gy/fraction) daily ◊◊60–66 Gy (1.8–2.0 Gy/fraction); daily Monday–Friday in Monday–Friday in 6–7 weeks2,3 6–6.5 weeks2 ––Concomitant boost accelerated RT: Low to intermediate risk: sites of suspected subclinical spread ▪▪72 Gy/6 weeks (2 Gy once daily and then 1.8 Gy/fraction, ◊◊ 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4,5 large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) POSTOPERATIVE CHEMORADIATION ▪▪66–70 Gy (2.0 Gy/fraction; 6 fractions/wk accelerated) • Concurrent systemic therapy6 ––Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4,5 CONCURRENT CHEMORADIATION:6 • PTV High-risk: typically 70–70.2 Gy (1.8–2.0 Gy/fraction); daily Monday–Friday in 7 weeks2 Low to intermediate risk: 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4,5 Either IMRT (preferred) or 3D conformal RT is recommended for maxillary sinus or paranasal/ethmoid sinus tumors to minimize dose to critical structures. Proton therapy can be considered when normal tissue constraints cannot be met by photon-based therapy.

4Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy 1See Radiation Techniques (RAD-A) and Discussion. with IMRT dose painting technique (dependent on dose per fraction). 2In the paranasal sinus area, care should be taken to avoid critical 5Treatment to sites of suspected subclinical spread is not consistently performed at all neural structures; therefore, 1.8 Gy/fraction can be considered. institutions. (Le QT, Fu KK, Kaplan MJ, et al. Lymph node metastasis in maxillary sinus 3For doses >70 Gy, some clinicians feel that the fractionation carcinoma. Int J Radiat Oncol Biol Phys 2000;46:541-549) and (Jeremic B, Nguyen-Tan should be slightly modified (eg, <2.0 Gy/fraction for at least PF, Bamberg M. Elective neck irradiation in locally advanced squamous cell carcinoma some of the treatment) to minimize toxicity. An additional 2–3 of the maxillary sinus: a review. J Cancer Res Clin Oncol 2002;128:235-238.) doses can be added depending on clinical circumstances. 6See Principles of Systemic Therapy (CHEM-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Very Advanced Head and Neck Cancer Discussion

DIAGNOSIS TREATMENT OF HEAD AND NECK CANCER

Clinical trial preferred

Concurrent systemic therapy/RTa,b,c Newly diagnosed (M0) PS 0-1 or T4b, any N Induction chemotherapya (category 3) or followed by RTb or systemic therapy/RTa,b Unresectable nodal disease See Follow-Up Recurrent or Definitive RTb Recommendations or PS 2 Unfit for surgery ± concurrent systemic therapya Post persistent Chemoradiation or disease RT (FOLL-A, 2 of 2) (See ADV-3) Palliative RTb or PS 3 Single-agent systemic therapya or Newly Best supportive care diagnosed disease

M1 disease at initial See ADV-2 presentation PS = Performance Status (Eastern Cooperative Oncology Group [ECOG])

aSee Principles of Systemic Therapy (CHEM-A). bSee Principles of Radiation Therapy (ADV-A). cWhen using concurrent systemic therapy/RT, the preferred agent is cisplatin (category 1). See Principles of Systemic Therapy (CHEM-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Very Advanced Head and Neck Cancer Discussion

DIAGNOSIS TREATMENT OF HEAD AND NECK CANCER PERSISTENT DISEASE OR PROGRESSION

Clinical trial preferred Combination systemic therapya Systemic or therapy,a Single-agent systemic therapya clinical trial or preferred PS 0-1 Surgeryd or RTb or systemic therapy/RTa,b or Consider for selected patients with limited metastases Best locoregional or supportive Metastatic (M1) treatment based Best supportive care care disease at initial on primary site presentation algorithms (See Table of Best a Contents) Single-agent systemic therapy supportive PS 2 or care Best supportive care

Distant metastases

PS 3 Best supportive care

aSee Principles of Systemic Therapy (CHEM-A). bSee Principles of Radiation Therapy (ADV-A). dSee Principles of Surgery (SURG-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Very Advanced Head and Neck Cancer Discussion

DIAGNOSIS TREATMENT OF HEAD AND NECK CANCER No adverse Follow-up f Observation d features (See FOLL-A) Surgery Extranodal Systemic therapy/RTa,b extension and/or (category 1) positive margin Adverse b featuresf RT Locoregional Resectable or Other risk or recurrence features Consider systemic without therapy/RTa,b prior RT Concurrent systemic therapy/RTa,b,c or Therapy for persistent Induction chemotherapya (category 3) disease as indicated followed by RTb or systemic therapy/RTa,b

See Treatment of Very Advanced Unresectable Recurrent Head and Neck Cancer (ADV-1) or persistent d b,g a,b disease Resectable Surgery ± postoperative reirradiation or systemic therapy/RT, Locoregional clinical trial preferred recurrence or second primary Reirradiationb ± systemic therapy,a clinical trial preferred with prior RT or Unresectable Systemic therapya (see ADV-4) or Best supportive care Distant See (ADV-4) metastasese fAdverse features: extranodal extension, positive margins, pT3 or pT4 primary, N2 aSee Principles of Systemic Therapy (CHEM-A). or N3 nodal disease, perineural invasion, vascular embolism, lymphatic invasion bSee Principles of Radiation Therapy (ADV-A). (See Discussion). cWhen using concurrent systemic therapy/RT, the preferred agent is cisplatin gReirradiation should be limited to a highly select subset of patients (Janot F, de (category 1). See Principles of Systemic Therapy (CHEM-A). Raucourt D, Benhamou E, et al. Randomized trial of postoperative reirradiation dSee Principles of Surgery (SURG-A). combined with chemotherapy after salvage surgery compared with salvage eConsider palliative RT as clinically indicated (eg, bone metastases). (See RAD-A). surgery alone in head and neck carcinoma. J Clin Oncol 2008;26:5518-5523).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Very Advanced Head and Neck Cancer Discussion

DIAGNOSIS TREATMENT PERSISTENT DISEASE OR PROGRESSION

Combination systemic therapya Clinical trial preferred or Systemic Single-agent systemic therapya therapy, clinical or trial preferred PS 0-1 Surgeryd or RTb or systemic therapy/RTa,b or for selected patients with limited metastases Best or supportive care Recurrent or Best supportive care If locoregional failure, consider persistent locoregional treatment based on disease with disease extent and symptoms distant (See ADV-3) metastases Single-agent systemic therapya Best supportive PS 2 or care Best supportive care

Distant metastases onlye

PS 3 Best supportive care

aSee Principles of Systemic Therapy (CHEM-A). dSee Principles of Surgery (SURG-A). bSee Principles of Radiation Therapy (ADV-A). eConsider palliative RT as clinically indicated (eg, bone metastases). (See RAD-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Very Advanced Head and Neck Cancer Discussion

PRINCIPLES OF RADIATION THERAPY1,2

CONCURRENT CHEMORADIATION3 (preferred for patients eligible for chemotherapy): • PTV High risk: typically 70 Gy (2.0 Gy/fraction) Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4 CHEMORADIATION:3 Based on published data, concurrent chemoradiation most commonly uses conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with single-agent cisplatin given every 3 weeks at 100 mg/m2; 2–3 cycles of chemotherapy are used depending on the radiation fractionation scheme (RTOG 0129) (Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24-35). When carboplatin and 5-FU are used, then the recommended regimen is standard fractionation plus 3 cycles of chemotherapy (Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol 2012;13:145-53). Other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, other dosing schedules of cisplatin, or altered fractionation with chemotherapy are efficacious, and there is no consensus on the optimal approach.5 Data indicate that accelerated fractionation does not offer improved efficacy over conventional fractionation.6,7 In general, the use of concurrent chemoradiation carries a high toxicity burden; altered fractionation or multiagent chemotherapy will likely further increase the toxicity burden. For any chemoradiation approach, close attention should be paid to published reports for the specific chemotherapy agent, dose, and schedule of administration. Chemoradiation should be performed by an experienced team and should include substantial supportive care.

1See Radiation Techniques (RAD-A) and Discussion. 3See Principles of Systemic Therapy (CHEM-A). 2In general, the reirradiated population of head and neck cancer patients described in 4Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54– current literature represents a diverse but highly selected group of patients treated 63 Gy with IMRT dose painting technique (dependent on dose per fraction). in centers where there is high level of expertise and systems in place for managing 5RTOG 0522: a randomized phase III trial of concurrent accelerated radiation acute and long-term toxicities. When the goal of treatment is curative and surgery is and cisplatin versus concurrent accelerated radiation, cisplatin, and not an option, reirradiation strategies can be considered for patients who: develop cetuximab [followed by surgery for selected patients] for stage III and IV head locoregional failures or second primaries at ≥6 months after the initial radiotherapy; can and neck carcinomas. Clin Adv Hematol Oncol 2007;5:79-81. receive additional doses of radiotherapy of at least 60 Gy; and can tolerate concurrent 6Ang K, Zhang Q, Wheeler RH, et al. A phase III trial (RTOG 0129) of two chemotherapy. Organs at risk for toxicity should be carefully analyzed through review radiation-cisplatin regimens for head and neck carcinomas (HNC): Impact of dose-volume histograms, and consideration for acceptable doses should be made of radiation and cisplatin intensity on outcome [abstract]. J Clin Oncol on the basis of time interval since original radiotherapy, anticipated volumes to be 2010;28(Suppl 15):Abstract 5507. included, and patient's life expectancy. Proton therapy can be considered when normal 7Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus tissue constraints cannot be met by photon-based therapy. (Takiar V, Garden AS, Ma acceleration of radiotherapy with or without concomitant chemotherapy in D, et al. Reirradiation of head and neck cancers with intensity modulated radiation locally advanced head and neck carcinoma (GORTEC 99-02): an open-label therapy: Outcomes and analyses. Int J Radiat Oncol Biol Phys 2016;95:1117-1131.) phase 3 randomised trial. Lancet Oncol 2012;13:145-153.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. ADV-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Very Advanced Head and Neck Cancer Discussion

PRINCIPLES OF RADIATION THERAPY1,2 DEFINITIVE: POSTOPERATIVE: RT Alone RT • PTV • Preferred interval between resection and postoperative RT is High risk: Primary tumor and involved lymph nodes (this includes ≤6 weeks. possible local subclinical infiltration at the primary site and at the • PTV high-risk level lymph node(s)) High risk: Adverse features such as positive margins ◊◊Fractionation: (See footnote f on ADV-3) ––70–72 Gy (2.0 Gy/fraction) daily Monday–Friday in 7–7.5 weeks8 ◊◊60–66 Gy (2.0 Gy/fraction); daily Monday–Friday in 6–6.5 weeks ––Concomitant boost accelerated RT: Low to intermediate risk: sites of suspected subclinical spread ▪▪72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4 second daily fraction during last 12 treatment days) ▪▪66–70 Gy (2.0 Gy/fraction; 6 fractions/wk accelerated) POSTOPERATIVE CHEMORADIATION: ––Hyperfractionation: 81.6 Gy/7 weeks • Concurrent systemic therapy3,9-11 (1.2 Gy/fraction, twice daily) ––Modified fractionation: total dose >70 Gy and treatment course <7 weeks Low to intermediate risk: sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4 Either IMRT or 3D conformal RT is recommended.

1See Radiation Techniques (RAD-A) and Discussion. 2 In general, the reirradiated population of head and neck cancer patients described 3See Principles of Systemic Therapy (CHEM-A). in current literature represents a diverse but highly selected group of patients 4Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy treated in centers where there is high level of expertise and systems in place for with IMRT dose painting technique (dependent on dose per fraction). managing acute and long-term toxicities. When the goal of treatment is curative 8For doses >70 Gy, some clinicians feel that the fractionation should be slightly and surgery is not an option, reirradiation strategies can be considered for modified (eg, <2.0 Gy/fraction for at least some of the treatment) to minimize patients who: develop locoregional failures or second primaries at ≥6 months toxicity. An additional 2–3 doses can be added depending on clinical circumstances. after the initial radiotherapy; can receive additional doses of radiotherapy of at 9Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without least 60 Gy; and can tolerate concurrent chemotherapy. Organs at risk for toxicity concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952. should be carefully analyzed through review of dose-volume histograms, and 10 consideration for acceptable doses should be made on the basis of time interval Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. since original radiotherapy, anticipated volumes to be included, and patient's life N Engl J Med 2004;350:1937-1944. expectancy. Proton therapy can be considered when normal tissue constraints 11Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head cannot be met by photon-based therapy. (Takiar V, Garden AS, Ma D, et al. and neck cancers: A comparative analysis of concurrent postoperative radiation Reirradiation of head and neck cancers with intensity modulated radiation therapy: plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck Outcomes and analyses. Int J Radiat Oncol Biol Phys 2016;95:1117-1131.) 2005;27:843-850.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. ADV-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Occult Primary Discussion

PRESENTATION PATHOLOGY WORKUP • CT with contrast or MRI with contrast (skull base through Treat as thoracic inlet) appropriate Primary • FDG-PET/CT as indicated (See NCCN Squamous cell found (before EUA) Guidelines carcinoma, • Chest CT with contrast (if PET/CT Index) adenocarcinoma, not done) and anaplastic/ • HPV, EBV testing for squamous undifferentiated cell or undifferentiated histologye See Workup epithelial tumorsd Primary • Thyroglobulin, calcitonin, and • H&Pa,b not PAX8, and/or TTF staining for Treatment • Complete head and foundf adenocarcinoma and anaplastic/ (OCC-2) neck exam with undifferentiated tumors attention to skin; palpation of the oropharynx; mirror Lymphoma See NCCN Guidelines for Non-Hodgkin’s Lymphomas Neck and fiberoptic FNAc mass examination as clinically indicated Thyroid See NCCN Guidelines for Thyroid Carcinoma to examine nasopharynx, Systemic workup per NCCN See Primary Treatment oropharynx, Guidelines for Melanoma for NCCN Guidelines hypopharynyx, • Skin exam, note regressing lesions for Melanoma Melanoma and larynx See Primary Therapy See Workup for Mucosal Melanoma (MM-1) for Mucosal Melanoma (MM-4) aH&P should include documentation and quantification (pack years smoked) of tobacco use history. Smoking cessation counseling as clinically indicated. All current smokers should be advised to quit smoking, and former smokers should be advised to remain abstinent from dDetermined with appropriate immunohistochemical stains. smoking. For additional cessation support and resources, smokers can be referred to the eWhether HPV or EBV positive status may help to define the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. radiation fields is being investigated (See Principles of Surgery bScreen for depression (See NCCN Guidelines for Distress Management). [SURG-A 2 of 8] and Discussion). cRepeat FNA, core, or open biopsy may be necessary for uncertain or non-diagnostic fStrongly consider referral to a high-volume, multidisciplinary histologies. Patient should be prepared for neck dissection at time of open biopsy, if indicated. cancer center.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Occult Primary Discussion

PATHOLOGIC WORKUP DEFINITIVE TREATMENT FINDINGS Primary Treat as appropriate found (See NCCN Guidelines Index)

• EUA • Palpation and inspection See Follow-Up Node level RTi to • Biopsy of areas of Neck dissection Recommendations I, II, III, neck ± clinical concern Levels I-III + parotidectomy, Post upper V parotid and tonsillectomy ± Adenocarcinoma if indicatedh Chemoradiation or bed lingual tonsillectomy of neck node, RT (FOLL-A, 2 of 2) • Direct laryngoscopy thyroglobulin and nasopharynx negative, Neck survey calcitonin dissection,h Evaluate for if indicated negative Follow-up Levels IV, V infraclavicular ± adjuvant • EUA including (See FOLL-A) direct laryngoscopy, primary treatment esophagoscopy, if indicated Node level bronchoscopy (see OCC-4) IV, lower V • Chest/abdominal/ Poorly differentiated pelvic CT with or nonkeratinizing contrast (or squamous cell FDG-PET/CT if or not otherwise not previously specified (NOS) See Definitive Treatment (OCC-3) performed) or anaplastic (not thyroid) of neck node or squamous cell carcinoma of neck nodeg

gHPV and EBV testing are suggested if not yet done. hSee Principles of Surgery (SURG-A). iSee Principles of Radiation Therapy (OCC-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Occult Primary Discussion

HISTOLOGY DEFINITIVE TREATMENT

Neck dissectionh (preferred for N1 disease, See OCC-4 single node ≤3 cm)

or Poorly differentiated or RTi for N1, single node ≤3 nonkeratinizing cm (category 2B) squamous cell or NOS or anaplastic or (not thyroid) or i,j Recurrent or Systemic therapy/RT See Follow-Up Recommendations Post Squamous cell persistent disease for ≥ N2 (category 2B) Chemoradiation or RT (FOLL-A, 2 of 2) carcinoma (See ADV-3) or

Induction chemotherapy for N2-3j,k (category 3) followed by systemic therapy/RTi,j or RTi

hSee Principles of Surgery (SURG-A). iSee Principles of Radiation Therapy (OCC-A). jSee Principles of Systemic Therapy (CHEM-A). kSee Discussion on induction chemotherapy.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Occult Primary Discussion

TREATMENT RTi (Target volume determined by tumor size, nodal N1 without extranodal station, and HPV and EBV status)e extension or Observe

RTi (Target volume determined by tumor size, nodal N2, N3 without e Post neck station, and HPV and EBV status) Follow-up extranodal dissection or (See FOLL-A) extension Consider systemic therapy/RTi,j (category 2B)

Recurrent or Systemic therapy/RTi,j (category 1) persistent Extranodal or disease extension RTi (Target volume determined by tumor size, nodal (See ADV-3) station, and HPV and EBV status)e

eWhether HPV or EBV positive status may help to define the radiation fields is being investigated (See Principles of Surgery [SURG-A 2 of 8] and Discussion). iSee Principles of Radiation Therapy (OCC-A). jSee Principles of Systemic Therapy (CHEM-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Occult Primary Discussion

PRINCIPLES OF RADIATION THERAPY1,2 DEFINITIVE: CONCURRENT CHEMORADIATION:5,6 RT Alone • PTV • PTV High risk: typically 70 Gy (2.0 Gy/fraction) High risk: Involved lymph nodes (this includes possible local Mucosal dosing: 50–60 Gy (2.0 Gy/fraction) to putative mucosal subclinical infiltration at the high-risk level lymph node(s)) primary sites, depending on field size and use of chemotherapy. ◊◊Fractionation: Consider higher dose to 60–66 Gy to particularly suspicious areas ––66 Gy (2.2 Gy/fraction) to 70 Gy (2.0 Gy/fraction); daily Low to intermediate risk: 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy Monday–Friday in 6–7 weeks3 (1.6–1.8 Gy/fraction)4 ––Mucosal dosing: 50–66 Gy (2.0 Gy/fraction) to putative mucosal sites, depending on field size. Consider higher dose to 60–66 Gy to particularly suspicious areas Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4

Either IMRT or 3D conformal RT is recommended when targeting the oropharynx to minimize the dose to critical structures.

1For squamous cell carcinoma, adenocarcinoma, and poorly differentiated carcinoma. 2See Radiation Techniques (RAD-A) and Discussion. 3For doses >70 Gy, some clinicians feel that the fractionation should be slightly modified (eg, <2.0 Gy/fraction for at least some of the treatment) to minimize toxicity. An additional 2–3 doses can be added depending on clinical circumstances. 4Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). 5See Principles of Systemic Therapy (CHEM-A). 6Based on published data, concurrent chemoradiation most commonly uses conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with single-agent cisplatin given every 3 weeks at 100 mg/m2; 2–3 cycles of chemotherapy are used depending on the radiation fractionation scheme (RTOG 0129) (Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24-35). When carboplatin and 5-FU are used, the recommended regimen is standard fractionation plus 3 cycles of chemotherapy. (Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol 2012;13:145-153). Other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, other dosing schedules of cisplatin, or altered fractionation with chemotherapy are efficacious, and there is no consensus on the optimal approach. In general, the use of concurrent chemoradiation carries a high toxicity burden; altered fractionation or multiagent chemotherapy will likely further increase the toxicity burden. For any chemoradiation approach, close attention should be paid to published reports for the specific chemotherapy agent, dose, and schedule of administration. Chemoradiation should be performed by an experienced team and should include substantial supportive care.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. OCC-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Occult Primary Discussion

PRINCIPLES OF RADIATION THERAPY1,2

POSTOPERATIVE: RT • Preferred interval between resection and postoperative RT is ≤6 weeks • PTV High risk: Adverse features such as extranodal extension (See OCC-4) ◊◊Mucosal dose: 50–66 Gy (2.0 Gy/fraction) to putative mucosal sites, depending on field size. Consider higher dose to 60–66 Gy to particularly suspicious areas Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)4

POSTOPERATIVE CHEMORADIATION: • Concurrent systemic therapy5,7-10

Either IMRT or 3D conformal RT is recommended when targeting the oropharynx to minimize the dose to critical structures.

1For squamous cell carcinoma, adenocarcinoma, and poorly differentiated carcinoma. 2See Radiation Techniques (RAD-A) and Discussion. 4Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). 5See Principles of Systemic Therapy (CHEM-A). 7Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952. 8Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-1944. 9Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843-850. 10Cooper JS, Zhang Q, Pajak TF et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012;84:1198-1205.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. OCC-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Salivary Gland Tumors Discussion

CLINICAL WORKUP PRESENTATION

• H&Pb,c including a complete head and neck exam; mirror and fiberoptic Unresected examination as clinically indicated Clinically benignf salivary gland • CT/MRI with contrast of skull base to or See SALI-2 mass clavicle, if clinically indicated Carcinoma • Parotid • Chest CT (with or without contrast) • Submandibular as clinically indicated • Minor salivary • FNA biopsy glanda • Dental evaluation as clinically indicatedd or • Nutritional evaluation as clinically indicatede Incompletely • Preanesthesia studies as clinically See NCCN Guidelines resected salivary indicated Lymphoma for Non-Hodgkin’s gland mass Lymphomas Multidisciplinary consultation as clinically indicated

aSite and stage determine therapeutic approaches. bH&P should include documentation and quantification (pack years smoked) of tobacco use history. Smoking cessation counseling as clinically indicated. All current smokers should be advised to quit smoking, and former smokers should be advised to remain abstinent from smoking. For additional cessation support and resources, smokers can be referred to the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. cScreen for depression (See NCCN Guidelines for Distress Management). dSee Principles of Dental Evaluation and Management (DENT-A). eSee Principles of Nutrition: Management and Supportive Care (NUTR-A). fCharacteristics of a benign tumor include mobile superficial lobe, slow growth, painless, V and/or VII intact, and no neck nodes.

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. SALI-1 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Salivary Gland Tumors Discussion

PATHOLOGY RESULT Follow-up as Benign clinically indicated or If tumor spillage or Low grade perineural invasion, consider RTi Recurrent f Complete Clinically benign or or g surgical Follow-up carcinoma, T1, T2 h Persistent resection (See FOLL-A) Disease Adenoid cystic; (See SALI-4) Consider RTi Intermediate or (category 2B for T1) high grade

Parotid gland

Surgical Cancer T3, T4a See Treatment evaluation site (SALI-3) Other salivary glands

Definitive RTi Recurrent No surgical resection or or Follow-up T4b possible or surgical Systemic Persistent (See FOLL-A) resection not recommended therapy/RT Disease (category 2B) (See SALI-4) fCharacteristics of a benign tumor include mobile superficial lobe, slow growth, no pain, VII intact, and no neck nodes. gIf incidental N+ disease is present go to SALI-3. hSurgical resection of a clinically benign tumor includes: no enucleation of lateral lobe and intraoperative communication with pathologist if indicated. iSee Principles of Radiation Therapy (SALI-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Salivary Gland Tumors Discussion

CANCER SITE TREATMENTk Recurrent No adverse Follow-up or Persistent features (See FOLL-A) Disease (See SALI-4) Surgery with complete Completely RTi resection of tumor Adenoid cystic resected (category 2B) ± neck dissectionl Clinical N0 for high-grade Adverse features: Adjuvant RTi Major salivary and/or T3-4 • Intermediate or high grade (preferred) gland (parotid, tumors • Close or positive margins or submandibular, • Neural/perineural invasion Systemic sublingual) • Lymph node metastases Surgery + neck therapy/RT Clinical N+ • Lymphatic/vascular invasion dissectionl (category 2B) • T3-4 tumors

Complete tumor Clinical N0 l Surgical resection l Minor resection, salivary if possible glandj Complete tumor resection and Incompletely Clinical N+ lymph node resected, gross dissectionl residual disease Definitive RTi or No further surgical Systemic resection possible therapy/RT (category 2B) iSee Principles of Radiation Therapy (SALI-A). jFor submandibular and sublingual gland tumors, complete gland and tumor resection is recommended. kThe facial nerve should be preserved if possible; strongly consider referral to a specialized center with reconstructive expertise. lSee Principles of Surgery (SURG-A).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Salivary Gland Tumors Discussion

RECURRENCE TREATMENT FOR RECURRENCE RTi Follow-up (see FOLL-A) Completely Resectable resected Adverse features: • Intermediate or high grade Adjuvant RTi Locoregional • Close or positive margins or recurrence • Neural/perineural invasion Consider systemic without • Lymph node metastases therapy/RT (category 2B) prior RT • Lymphatic/vascular invasion

RTi Unresectable or Systemic therapy/RT (category 2B)

Surgeryl (preferred) Locoregional Resectable or Reirradiation ± chemotherapy, clinical trial preferred Follow-up recurrence or (See FOLL-A) second primary Reirradiation ± chemotherapy, clinical trial preferred with prior RT Unresectable or Chemotherapy (see Distant metastases pathway below)

Chemotherapy Clinical trial preferred or Expectant management (with slow-growing disease) Distant or m metastases Selected metastasectomy (category 3) PS 0-3 or Androgen receptor therapy (eg, leuprolide, bicalutamide) if AR+ or Trastuzumab if HER2+ (category 2B) or Best supportive care iSee Principles of Radiation Therapy (SALI-A). lSee Principles of Surgery (SURG-A). mCheck androgen receptor (AR) status and HER2 status prior to treatment for distant metastases. PS = Performance Status (ECOG)

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. SALI-4 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Salivary Gland Tumors Discussion

PRINCIPLES OF RADIATION THERAPY1,2,3

DEFINITIVE: RT Alone • Photon or photon/electron therapy or highly conformal radiation therapy techniques • PTV: High risk: Primary tumor and involved lymph nodes (this includes possible local subclinical infiltration at the primary and at the high-risk level lymph node(s)) ◊◊Fractionation: 66 Gy (2.0 Gy/fraction) to 70–70.2 Gy (1.8–2.0 Gy/fraction); daily Monday–Friday in 6–7 weeks4 Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)5

POSTOPERATIVE RT: • Preferred interval between resection and postoperative RT is ≤6 weeks • Photon or photon/electron therapy • PTV High risk: Adverse features such as positive margins (see SALI-3) ◊◊60–66 Gy (2.0 Gy/fraction); daily Monday–Friday in 6–7 weeks Low to intermediate risk: Sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction)5 Either IMRT or 3D conformal RT is recommended. Proton therapy can be considered when normal tissue constraints cannot be met by photon-based therapy. 1See Radiation Techniques (RAD-A) and Discussion. 2Neutron therapy was historically considered a promising solution for unresectable salivary gland cancers, but this therapy is currently offered at only one center in the United States. Pfister DG, Spencer S, Brizel DM, et al. NCCN Head and Neck Cancers, Version 1.2015. J Natl Compr Canc Netw 2015;13:847-856. 3In general, the reirradiated population of head and neck cancer patients described in current literature represents a diverse but highly selected group of patients treated in centers where there is high level of expertise and systems in place for managing acute and long-term toxicities. When the goal of treatment is curative and surgery is not an option, reirradiation strategies can be considered for patients who: develop locoregional failures or second primaries at ≥6 months after the initial radiotherapy; can receive additional doses of radiotherapy of at least 60 Gy; and can tolerate concurrent chemotherapy. Organs at risk for toxicity should be carefully analyzed through review of dose-volume histograms, and consideration for acceptable doses should be made on the basis of time interval since original radiotherapy, anticipated volumes to be included, and patient's life expectancy. Proton therapy can be considered when normal tissue constraints cannot be met by photon-based therapy. (Takiar V, Garden AS, Ma D, et al. Reirradiation of head and neck cancers with intensity modulated radiation therapy: Outcomes and analyses. Int J Radiat Oncol Biol Phys 2016;95:1117-1131.) 4For doses >70 Gy, some clinicians feel that the fractionation should be slightly modified (eg, <2.0 Gy/fraction for at least some of the treatment) to minimize toxicity. An additional 2–3 doses can be added depending on clinical circumstances. 5Suggest 44–50 Gy in 3D conformal RT and sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Mucosal Melanoma Discussion

PRESENTATION WORKUP TREATMENT

• H&Pa,b including complete head and neck exam; mirror and fiberoptic examination as clinically indicated • Verification of pathology using appropriate staining Sinus or nasal cavity See Primary (HMB-45, S-100, Melan-A) mucosal melanoma Treatment (MM-2) • CT with contrast and/or MRI with Biopsy contrast to determine anatomic extent confirms of disease, particularly for sinus diagnosis of disease mucosal • Chest CT (with or without contrast) as malignant clinically indicated melanoma • Consider FDG-PET/CT or chest/ Oral cavity, oropharynx, See Primary abdominal/pelvic CT with contrast, and larynx, or hypopharynx Treatment (MM-3) brain MRI (with and without contrast) to mucosal melanoma rule out metastatic disease

Multidisciplinary consultation as clinically indicated

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Mucosal Melanoma Discussion

PRIMARY ADJUVANT TREATMENT TREATMENT

Strongly consider Stage III Surgical resection of primaryc postoperative RTd to primary site

Stage IVA, Postoperative RTd Surgical resectionc T4a, N0 to primary site Follow-up (See FOLL-A) Recurrent Postoperative RTd or Sinus or nasal cavity Stage IVA, Surgical resection to primary site and persistent mucosal melanoma T3-T4a, N1 + neck dissection of positive neckc neck disease, see NCCN Clinical trial (preferred) Guidelines or for Stage IVB Primary RTd See Follow-Up Recommendations Post Melanoma or Chemoradiation or RT (FOLL-A, 2 of 2) Systemic therapye

Clinical trial (preferred) or Best supportive care Stage IVC or Primary RTd or Systemic therapye

cSee Principles of Surgery (SURG-A). dSee Principles of Radiation Therapy (MM-A). eSee Systemic Therapy for Metastatic or Unresectable Disease (page ME-H) from the NCCN Guidelines for Melanoma.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Mucosal Melanoma Discussion

PRIMARY TREATMENT ADJUVANT FOLLOW-UP TREATMENT

Surgical resection, Strongly consider Stage III + neck dissectionc postoperative RTd

Follow-up Surgical resection d (See FOLL-A) Stage IVA c Postoperative RT + neck dissection Recurrent or persistent Oral cavity, oropharynx, disease, see NCCN larynx, or hypopharynx Clinical trial (preferred) Guidelines for Melanoma mucosal melanoma or Stage IVB Primary RTd See Follow-Up Recommendations and/or Post Chemoradiation or RT Systemic therapye (FOLL-A, 2 of 2)

Clinical trial (preferred) or Best supportive care Stage IVC or Primary RTd or Systemic therapye

cSee Principles of Surgery (SURG-A). dSee Principles of Radiation Therapy (MM-A). eSee Systemic Therapy for Metastatic or Unresectable Disease (page ME-H) from the NCCN Guidelines for Melanoma.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Mucosal Melanoma Discussion

PRIMARY THERAPY FOR OCCULT PRIMARY- MELANOMA (Also see NCCN Guidelines for Occult Primary)

± RT to nodal basin for ± Adjuvant systemic therapy, per Nodal basin Nodal dissectionc high-risk featuresd,f NCCN Guidelines for Melanoma

cSee Principles of Surgery (SURG-A). dSee Principles of Radiation Therapy (MM-A). fHigh-risk: adverse features: >2 nodes, single node >3 cm, extranodal extension, recurrence in nodal basin after previous surgery.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Mucosal Melanoma Discussion

PRINCIPLES OF RADIATION THERAPY1,2

DEFINITIVE: RT Alone (unresectable locally advanced melanoma): • PTV: High risk: Primary tumor and involved lymph nodes (this includes possible local subclinical infiltration at the primary site and at the high-risk-level lymph node(s) ◊◊66 Gy (2.2 Gy/fraction) to 70 Gy (2.0 Gy/fraction) daily Monday–Friday in 6–7 weeks Low to intermediate risk: Sites suspected of subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction) • Palliative RT doses and schedules may be considered. • Optional dosing schedules may be considered.3

POSTOPERATIVE: RT: • Preferred interval between resection and postoperative RT is <6 weeks. • PTV High risk: adverse features >2 nodes, single node >3 cm, extranodal extension, recurrence in nodal basin after previous surgery2 ◊◊60–66 Gy (2.0 Gy/fraction; daily Monday–Friday) in 6–6.5 weeks Low to intermediate risk: sites of suspected subclinical spread ◊◊44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction) • Optional dosing schedules may be considered.3

Either IMRT or 3D conformal RT is recommended. Proton therapy can be considered when normal tissue constraints cannot be met by photon-based therapy.

1See Radiation Techniques (RAD-A) and Discussion. 2Recent studies suggest that increased toxicity may occur when RT is used in combination with BRAF inhibitors. (Anker CJ, Grossmann KF, Atkins MB, et al. Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: Consensus guidelines from the Eastern Cooperative Oncology Group (ECOG). Int J Radiat Oncol Biol Phys 2016;95:632-646.) 3Optional dose schedules include 48–50 Gy (2.4–3.0 Gy/fraction) and 30–36 Gy (6 Gy/fraction). (Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol 2012;13:589-597; Ballo MT, Bonnen MD, Garden AS, et al. Adjuvant irradiation for cervical node metastases from melanoma. Cancer 2003;97:1789-1796; and Moreno MA, Roberts DB, Kupferman ME, et al. Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center. Cancer 2010;116:2215-2213).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

FOLLOW-UP RECOMMENDATIONS1 (based on risk of relapse, second primaries, treatment sequelae, and toxicities) • H&P exam (including a complete head and neck exam; and mirror and fiberoptic examination):2 Year 1, every 1–3 mo Year 2, every 2–6 mo Years 3–5, every 4–8 mo >5 years, every 12 mo • Imaging: Post-treatment, consider repeating pre-treatment baseline imaging of primary (and neck, if treated) within 6 mo of treatment (category 2B). Chest CT with or without contrast as clinically indicated for patients with smoking history (See NCCN Guidelines for Lung Cancer Screening). Further reimaging as indicated based on worrisome or equivocal signs/symptoms, smoking history, and areas inaccessible to clinical examination. Routine annual imaging (repeat use of pretreatment imaging modality) may be indicated in areas difficult to visualize on exam. • Thyroid-stimulating hormone (TSH) every 6–12 mo if neck irradiated. • Dental evaluation3 for oral cavity and sites exposed to significant intraoral radiation treatment. • Consider EBV DNA monitoring for nasopharyngeal cancer (category 2B). • Supportive care and rehabilitation: Speech/hearing and swallowing evaluation4 and rehabilitation as clinically indicated. Nutritional evaluation and rehabilitation as clinically indicated until nutritional status is stabilized.4 Ongoing surveillance for depression (See NCCN Guidelines for Distress Management). Smoking cessation5 and alcohol counseling as clinically indicated. • Integration of survivorship care and care plan within 1 year, complementary to ongoing involvement from a head and neck oncologist (See NCCN Guidelines for Survivorship).6

1Most recurrences are reported by the patient. 5All current smokers should be advised to quit smoking, and former smokers should be advised 2For mucosal melanoma and paranasal sinus cancers, a physical exam to remain abstinent from smoking. For additional cessation support and resources, smokers should include endoscopic inspection for paranasal sinus disease. can be referred to the NCCN Guidelines for Smoking Cessation and www.smokefree.gov. 3See Principles of Dental Evaluation and Management (DENT-A). 6Cohen EE, LaMonte SJ, Erb NL, et al. American Cancer Society Head and Neck Cancer 4See Principles of Nutrition (NUTR-A). Survivorship Care Guideline. CA Cancer J Clin 2016;66:203-239.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. FOLL-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

FOLLOW-UP RECOMMENDATIONS POST CHEMORADIATION OR RT NECK EVALUATION7 To assess extent of disease or distant metastases: Residual • Consider CT of primary, primary and neck If diagnosis Resection of residual persistent and/or MRI with confirmed or primary and/or neck disease or contrast (4–8 wk) progression dissection progression • Consider FDG-PET/ CT No lymph node or node <1 cm; FDG- Observation 9 To assess extent of PET/CT negative After disease or distant If imaging Observation or neck 4–8 weeks Lymph node <1 systemic metastases: is positive, dissection: clinical CT of cm; FDG-PET/ therapy/RT 10 • Consider See assessment 8 primary CT positive or • FDG-PET/CT at ultrasound FNA Follow-up as minimum 12 wk and neck RT • Patient/surgeon (FOLL-A, appropriate or MRI Lymph node >1 decision with cm; FDG-PET/ 1 of 2) 9 • Consider amount contrast CT negative of nodal regression or Lymph node >1 If response cm; FDG-PET/ Neck dissection CT positive10 Neck dissection or • CT of primary and Imaging positive neck and/or MRI Consider FDG-PET with contrast at imaging at 12 wk 8–12 wk Imaging negative Observation

7Adapted with permission from Kutler DI, Patel SG, Shah JP. The role of neck dissection following definitive chemoradiation. Oncology 2004;18:993-998. 8If a FDG-PET/CT is performed and negative for suspicion of persistent cancer, further cross-sectional imaging is optional. 9PET negative = No or low-grade uptake, felt not suspicious for disease. 10PET positive = PET suspicious for disease.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. FOLL-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SURGERY Evaluation All patients should be evaluated by a head and neck surgical oncologist prior to treatment to assure the following: • Review the adequacy of biopsy material, review staging and imaging to determine the extent of disease, exclude the presence of a synchronous primary tumor, assess current functional status, and evaluate for potential surgical options, including those applicable if initial non-surgical treatment is unsuccessful. • Participate in the multidisciplinary team discussions regarding patient treatment options with the goal of maximizing survival with preservation of form and function. • Develop a prospective surveillance plan that includes adequate dental, nutritional, and health behavior evaluation and intervention and any other ancillary evaluations that would provide for comprehensive rehabilitation. • For patients undergoing an operation, the surgical procedure, margins, and reconstructive plan should be developed and designed to resect all gross tumors with adequate tumor-free surgical margins. The surgical procedure should not be modified based on any response observed as a result of prior therapy except in instances of tumor progression that mandate a more extensive procedure in order to encompass the tumor at the time of definitive resection.

Integration of Therapy • It is critical that multidisciplinary evaluation and treatment be coordinated and integrated prospectively by all disciplines involved in patient care before the initiation of any treatment.

Assessment of Resectability Tumor involvement of the following sites is associated with poor prognosis or function* or with T4b cancer (ie, unresectable based on technical ability to obtain clear margins). None of these sites of involvement is an absolute contraindication to resection in selected patients in whom total cancer removal is possible: • Involvement of the pterygoid muscles, particularly when associated with severe trismus or pterygopalatine fossa involvement with cranial neuropathy;* • Gross extension of the tumor to the skull base (eg, erosion of the pterygoid plates or sphenoid bone, widening of the foramen ovale); • Direct extension to the superior nasopharynx or deep extension into the Eustachian tube and lateral nasopharyngeal walls; • Invasion (encasement) of the common or internal carotid artery. Encasement is usually assessed radiographically and is defined as a tumor surrounding the carotid artery by 270 degrees or greater; • Direct extension of neck disease to involve the external skin;* • Direct extension to mediastinal structures, prevertebral fascia, or cervical vertebrae; and* • Presence of subdermal metastases.

*In selected cases, surgery might still be considered. Continued

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SURG-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 8 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SURGERY Primary Tumor Resection The resection of advanced tumors of the oral cavity, oropharynx, hypopharynx, larynx, or paranasal sinus will vary in extent depending on the structures involved. The primary tumor should be considered surgically curable by appropriate resection using accepted criteria for adequate excision, depending on the region involved. • En bloc resection of the primary tumor should be attempted whenever feasible. • In-continuity neck dissection is necessary when there is direct extension of the primary tumor into the neck. • Surgical resection should be planned based on the extent of the primary tumor as ascertained by clinical examination and careful interpretation of appropriate radiographic images. • For oral cavity cancers, as thickness of the lesion increases, the risk of regional metastases and the need for adjuvant elective neck dissection also increases. • Perineural invasion should be suspected when tumors are adjacent to motor or sensory nerves. The goal is total cancer resection. When gross invasion is present and the nerve can be resected without significant morbidity, the nerve should be dissected both proximally and distally and should be resected to obtain clearance of disease (See Surgical Management of Cranial Nerves page 4 of 8). Frozen section determination of the proximal and distal nerve margins may prove helpful to facilitate tumor clearance. • Partial or segmental resection of the mandible may be necessary to adequately encompass the cancer with adequate tumor-free margins. Adequate resection may require partial, horizontal, or sagittal resection of the mandible for tumors involving or adherent to mandibular periosteum. Segmental or marginal resection should be considered in tumors that grossly involve mandibular periosteum (as determined by tumor fixation to the mandible) or show evidence of direct tumor involvement of the bone at the time of operation or through preoperative imaging (CT/MRI/Panorex). The extent of mandibular resection will depend on the degree of involvement accessed clinically and in the operating room. • Medullary space invasion is an indication for segmental resection. Frozen section examination of available marrow may be considered to guide resection. • For tumors of the larynx, the decision to perform either total laryngectomy or conservation laryngeal surgery (eg, transoral resection, hemilaryngectomy, supraglottic laryngectomy) will be decided by the surgeon but should adhere to the principles of complete tumor extirpation with curative intent and function preservation. • For maxillary sinus tumors, note that “Ohngren’s line” runs from the medial canthus of the eye to the angle of the mandible, helping to define a plane passing through the maxillary sinus. Tumors “below” or “before” this line involve the maxillary infrastructure. Those “above” or “behind” Ohngren’s line involve the suprastructure. • Transoral robotic surgery (TORS) or laser-assisted resections of primary cancers in the oral cavity, larynx, and pharynx are increasingly used approaches for cancer resection in selected patients with limited disease and accessible tumors. Oncologic principles are similar to open procedures. Successful application of these techniques requires specialized skills and experience.

Continued

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SURG-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 8 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SURGERY Margins An overarching goal of oncologic surgery is complete tumor resection with histologic verification of tumor-free margins. Margin assessment may be in real time by frozen section or by assessment of formalin-fixed tissues. Tumor-free margins are an essential surgical strategy for diminishing the risk for local tumor recurrence. Conversely, positive margins increase the risk for local relapse and are an indication for postoperative adjuvant therapy. Clinical pathologic studies have demonstrated the significance of close or positive margins and their relationship with local tumor recurrence.1 When there is an initial cut-through with an invasive tumor at the surgical margin, obtaining additional adjacent margins from the patient may also be associated with a higher risk for local relapse. Obtaining additional margins from the patient is subject to ambiguity regarding whether the tissue taken from the surgical bed corresponds to the actual site of margin positivity.2 If positive surgical margins are reported, surgical re-resection and/or adjuvant therapy should be considered in selected patients. Frozen section margin assessment is always at the discretion of the surgeon and should be considered when it will facilitate complete tumor removal. The achievement of adequate wide margins may require resection of an adjacent structure in the oral cavity or laryngopharynx such as the base of the tongue and/or anterior tongue, mandible, larynx, or portions of the cervical esophagus. • Adequate resection is defined as clear resection margins with at least enough clearance from the gross tumor to obtain clear frozen section and permanent margins (often 1.5–2 cm of visible and palpable normal mucosa). However, for glottic cancers, a 1- to 2-mm margin is considered adequate. In general, frozen section examination of the margins will usually be undertaken intraoperatively, and, importantly, when a line of resection has uncertain clearance because of indistinct tumor margins, or there is suspected residual disease (ie, soft tissue, cartilage, carotid artery, mucosal irregularity). In transoral laser microsurgery, margins of 1.5–2.0 mm may be achieved with the goal of complete tumor resection with maximal normal tissue preservation. With this approach, adequacy of resection may be uncertain and is assessed under high magnification and confirmed intraoperatively by frozen sections.3 Such margins would be considered “close” and may be inadequate for certain sites such as oral tongue. • The details of resection margins should be included in the operative dictation. The margins may be assessed on the resected specimen or alternatively from the surgical bed with proper orientation. • A clear margin is defined as the distance from the invasive tumor front that is 5 mm or more from the resected margin. • A close margin is defined as the distance from the invasive tumor front to the resected margin that is less than 5 mm. • A positive margin is defined as carcinoma in situ or as invasive carcinoma at the margin of resection. If carcinoma in situ is present and if additional margins can be obtained that is the favored approach. Carcinoma in situ should not be considered an indication for concurrent postoperative chemoradiation. • The primary tumor should be marked in a fashion adequate for orientation by the surgical pathologist. The primary tumor should be assessed histologically for depth of invasion and for distance from the invasive portion of the tumor to the margin of resection, including the peripheral and deep margins. The pathology report should be template driven and describe how the margins were assessed. The report should provide information regarding the primary specimen to include the distance from the invasive portion of the tumor to the peripheral and deep margin. If the surgeon obtains additional margins from the patient, the new margins should refer back to the geometric orientation of the resected tumor specimen with a statement by the pathologist that this is the final margin of resection and its histologic status. • The neck dissection should be oriented or sectioned in order to identify levels of lymph nodes encompassed in the dissection. • Reconstruction of surgical defects should be performed using conventional techniques at the discretion of the surgeon. Primary closure is recommended when appropriate but should not be pursued at the expense of obtaining wide, tumor-free margins. Reconstructive closure with local/regional flaps, free-tissue transfer, or split-thickness skin or other grafts with or without mandibular reconstruction is performed at the discretion of the surgeon. Continued

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SURG-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 3 OF 8 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SURGERY

Surgical Management of Cranial Nerves VII, X (including the recurrent laryngeal nerve), XI, and XII Operative management of the facial nerve and other major cranial nerves during primary or regional node resection is influenced by the preoperative clinical function of the nerve.

• When the nerve is functioning, thorough efforts should be made to preserve the structure and function of the nerve (main trunk and/or branches)—even if otherwise adequate tumor margins are not achieved—recognizing that the surgeon should leave no gross residual disease. • Adjuvant postoperative radiation or chemoradiation is generally prescribed when a microscopic residual or gross residual tumor is suspected. • Direct nerve invasion by a tumor and/or preoperative paralysis of the nerve may warrant segmental resection (and sometimes nerve grafting) at the discretion of the surgeon if tumor-free margins are assured throughout the remainder of the procedure.

Continued

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SURG-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 4 OF 8 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SURGERY Neck Management The surgical management of regional lymphatics is dictated by the extent of the tumor at initial tumor staging. These guidelines apply to the performance of neck dissections as part of treatment of the primary tumor. In general, patients undergoing surgery for resection of the primary tumor will undergo dissection of the ipsilateral side of the neck that is at greatest risk for metastases. • Tumor sites that frequently have bilateral lymphatic drainage (eg, base of tongue, palate, supraglottic larynx, hypopharynx, nasopharynx, deep pre-epiglottic space involvement) often should have both sides of the neck dissected with the extent of dissection determined as suggested below. For those patients with tumors at or approaching the midline, both sides of the neck are at risk for metastases, and bilateral neck dissections should be performed. Patients with advanced lesions involving the anterior tongue, floor of the mouth, or alveolus that approximate or cross the midline should undergo contralateral selective/modified neck dissection as necessary to achieve adequate tumor resection. • Elective neck dissection should be based on risk of occult metastasis in the appropriate nodal basin. For oral cavity squamous cell carcinoma, SLN biopsy or the primary tumor depth of invasion is currently the best predictor of occult metastatic disease and should be used to guide decision making. For tumors with a depth greater than 4 mm, elective dissection should be strongly considered if RT is not already planned. For a depth less than 2 mm, elective dissection is only indicated in highly selective situations. For a depth of 2–4 mm, clinical judgment (as to reliability of follow-up, clinical suspicion, and other factors) must be utilized to determine appropriateness of elective dissection. Recent randomized trial evidence supports the effectiveness of elective neck dissection in patients with oral cavity cancers >3 mm in depth of invasion.4 Elective dissections are generally selective, preserving all major structures, unless operative findings dictate otherwise. • The type of neck dissection (comprehensive or selective) is defined according to preoperative clinical staging, is determined at the discretion of the surgeon, and is based on the initial preoperative staging as follows: N0 Selective neck dissection -Oral cavity at least levels I-III -Oropharynx at least levels II-IV -Hypopharynx at least levels II-IV and level VI when appropriate -Larynx at least levels II-IV and level VI when appropriate N1-N2a-c Selective or comprehensive neck dissection (See Discussion) N3 Comprehensive neck dissection

Continued

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SURG-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 5 OF 8 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SURGERY

Neck Management (continued) • Level VI neck dissections are performed for certain primary sites (such as the larynx and hypopharynx) as required to resect the primary tumor and any clinically evident neck nodes. Elective dissection depends on primary tumor extent and site. For advanced glottic and hypopharyngeal cancers treated with primary surgery, a level VI dissection (including pretracheal lymph nodes, the delphian lymph node, and unilateral or bilateral paratracheal lymph nodes) and hemithyroidectomy to total thyroidectomy is appropriate. For primary subglottic tumors or glottic cancers with significant subglottic extension, a level VI dissection with unilateral or total thyroidectomy is considered appropriate based on the extent of the primary tumor. For example, a T4a glottic tumor with extension through the cricothyroid membrane and subglottic extension should include a total thyroidectomy and pretracheal and bilateral paratracheal lymph node dissection. Parathyroid glands should be preserved in situ or auto transplanted as indicated.

Sentinel Lymph Node Biopsy • SLN biopsy is an alternative to elective neck dissection for identifying occult cervical metastasis in patients with early (T1 or T2) oral cavity carcinoma in centers where expertise for this procedure is available. Its advantages include reduced morbidity and an improved cosmetic outcome. Rates of detection of sentinel nodes in excess of 95% have been widely reported.4-6 Patients with metastatic disease in their sentinel nodes must undergo a completion neck dissection while those without may be observed. Accuracy of sentinel node biopsy for nodal staging of early oral carcinoma has been tested extensively in multiple single-center studies and two multi-institutional trials against the reference standard of immediately performed neck dissection or subsequent extended follow-up with a pooled estimate of sensitivity of 0.93 and negative predictive values ranging from 0.88 to 1.5-10 While direct comparisons with the policy of elective neck dissection are lacking, available evidence points towards comparable survival outcomes.10 • Sentinel node biopsy is a technically demanding procedure. Procedural success rates for sentinel node identification as well as accuracy of detecting occult lymphatic metastasis depend on technical expertise and experience. Hence, sufficient caution must be exercised when offering it as an alternative to elective neck dissection. This is particularly true in cases of floor-of-mouth cancer where accuracy of sentinel node biopsy has been found to be lower than for other locations such as the tongue.4,5 Also, cancers of certain locations such as upper gingiva and hard palate may not lend themselves well technically to this procedure. Likewise, occult cervical metastases are uncommon in early lip cancer, but SLN has been shown to be feasible and effective in patients with lip cancers deemed to be at high risk of metastases generally based on tumor size or depth.11

Continued

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SURG-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 6 OF 8 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SURGERY

Management of Recurrences Surgically resectable primary cancers should be re-resected with curative intent if feasible, and recurrences in a previously treated neck should undergo surgery as well. Neck disease in an untreated neck should be addressed by formal neck dissection or modification depending on the clinical situation. Non-surgical therapy may also be utilized as clinically appropriate.

Surveillance All patients should have regular follow-up visits to assess for symptoms and possible tumor recurrence, health behaviors, nutrition, dental health, and speech and swallowing function.

• Tumor evaluations must be performed by specialists skilled in head and neck clinical examination. • The frequency of evaluation is summarized elsewhere in the NCCN Guidelines for Head and Neck Cancers. See Follow-up Recommendations (FOLL-A 1 of 2). • For post chemoradiation or RT neck evaluations, see Follow-up Recommendations: Post Chemoradiation or RT Neck Evaluation (FOLL-A 2 of 2).

Continued

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SURG-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 7 OF 8 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SURGERY (References)

1Looser KG, Shah JP, Strong EW. The significance of “positive” margins in surgically resected epidermoid carcinomas. Head Neck Surg 1978;1:107-111. 2Scholl P, Byers RM, Batsakis JG, et al. Microscopic cut-through of cancer in the surgical treatment of squamous carcinoma of the tongue. Prognostic and therapeutic implications. Am J Surg 1986;152:354-360. 3Hinni ML, Zarka MA, Hoxworth JM. Margin mapping in transoral surgery for head and neck cancer. Laryngoscope 2013;123:1190-1198. 4Civantos FJ, Zitsch RP, Schuller DE et al. Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial. J Clin Oncol 2010;28:1395-400. 5Alkureishi LW, Ross GL, Shoaib T et al. Sentinel node biopsy in head and neck squamous cell cancer: 5-year follow-up of a European multicenter trial. Ann Surg Oncol 2010;17:2459-2464. 6Govers TM, Hannink G, Merkx MA, Takes RP, Rovers MM. Sentinel node biopsy for squamous cell carcinoma of the oral cavity and oropharynx: a diagnostic meta- analysis. Oral Oncol 2013;49:726-732. 7Pezier T, Nixon IJ, Gurney B et al. Sentinel lymph node biopsy for T1/T2 oral cavity squamous cell carcinoma—a prospective case series. Ann Surg Oncol 2012;19:3528-3533. 8Broglie MA, Haerle SK, Huber GF, Haile SR, Stoeckli SJ. Occult metastases detected by sentinel node biopsy in patients with early oral and oropharyngeal squamous cell carcinomas: impact on survival. Head Neck 2013;35:660-666. 9Samant S. Sentinel node biopsy as an alternative to elective neck dissection for staging of early oral carcinoma. Head Neck 2013 Jun 1 Epub ahead of print. 10D’Cruz AK, Vaish R, Kapre N, et al; Head and Neck Disease Management Group. Elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med 2015;373:521-529. 11Sollamo EM, Ilmonen SK, Virolainen MS, Suominen SH. Sentinel lymph node biopsy in cN0 squamous cell carcinoma of the lip: A retrospective study. Head Neck 2016;38 Suppl 1:E1375-80.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. SURG-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 8 OF 8 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

RADIATION TECHNIQUES1-8

Target delineation and optimal dose distribution require experience in head and neck imaging and a thorough understanding of patterns of disease spread. Standards for target definition, dose specification, fractionation (with and without concurrent chemotherapy), and normal tissue constraints are still evolving. IMRT or other conformal techniques (3D conformal RT, helical tomotherapy, volumetric modulated arc therapy [VMAT], and proton beam therapy [PBT]) may be used as appropriate depending on the stage, tumor location, physician training/ experience, and available physics support.* Close interplay exists between radiation technology, techniques, fractionation, and chemotherapy options resulting in a large number of combinations that may impact toxicity or tumor control. Close cooperation and interdisciplinary management are critical to treatment planning and radiation targeting, especially in the postoperative setting or after induction chemotherapy.9 FDG-PET/CT or MRI with contrast can be used for fusion in treatment planning.

Advanced radiation therapy technologies such as IMRT, image-guided radiation therapy (IGRT), and PBT may offer clinically relevant advantages in specific instances to spare important organs at risk (OARs), such as the brain, brain stem, cochlea, semicircular canals, optic chiasm and nerves, other cranial nerves, retina, lacrimal glands, cornea, spinal cord, brachial plexus, mucosa, salivary glands, bone (skull base and mandible), pharyngeal constrictors, larynx, and esophagus, and decrease the risk for late, normal tissue damage while still achieving the primary goal of local tumor control. The demonstration of significant dose-sparing of these OARs reflects best clinical practice.

Since the advantages of these techniques include tightly conformal doses and steep gradients next to normal tissues, target definition and delineation and treatment delivery verification require careful monitoring to avoid the risk of tumor geographic miss and subsequent decrease in local tumor control. Initial diagnostic imaging with contrast-enhanced CT, MRI, PET, and other imaging modalities facilitate target definition. Image guidance is required to provide assurance of accurate daily delivery.

Randomized studies to test these concepts are unlikely to be done since the above specific clinical scenarios are relatively rare. In light of that, the modalities and techniques that are found best to reduce the doses to the OARs in a clinically meaningful way without compromising target coverage should be considered.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. RAD-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

RADIATION TECHNIQUES

Intensity-Modulated Radiation Therapy (IMRT) IMRT has been shown to be useful in reducing long-term toxicity in oropharyngeal, paranasal sinus, and nasopharyngeal cancers by reducing the dose to salivary glands, temporal lobes, auditory structures (including cochlea), and optic structures. The application of IMRT to other sites (eg, oral cavity, larynx, hypopharynx, salivary glands) is evolving and may be used at the discretion of treating physicians. Helical tomotherapy and VMAT are advanced forms of IMRT.

IMRT, PBT, and Fractionation10-12 A number of ways exist to integrate IMRT or PBT, target volume dosing, and fractionation. The Simultaneous Integrated Boost (SIB) technique uses differential “dose painting” (66–72 Gy to gross disease; 44–63 Gy to subclinical disease) for each fraction of treatment throughout the entire course of radiation.4 SIB is commonly used in the conventional (5 fractions/wk) and the “6 fractions/wk accelerated” schedule.5 The Sequential (SEQ) technique typically delivers the initial (lower dose) phase (weeks 1–5) followed by the high-dose boost volume phase (weeks 6–7) using 2–3 separate dose plans, and is commonly applied in standard fractionation and hyperfractionation. The Concomitant Boost Accelerated schedule may utilize a “Modified SEQ” dose plan by delivering the dose to the subclinical targets once a day for 6 weeks, and a separate boost dose plan as a second daily fraction for the last 12 treatment days.6

Proton Beam Therapy (PBT) Achieving highly conformal dose distributions is especially important for patients whose primary tumors are periocular in location and/ or invade the orbit, skull base, and/or cavernous sinus; extend intracranially or exhibit extensive perineural invasion; and who are being treated with curative intent and/or who have long life expectancies following treatment. Nonrandomized single institution clinical reports and systematic comparisons demonstrate safety and efficacy of PBT in the above-mentioned specific clinical scenarios.29-49 Proton therapy can be considered when normal tissue constraints cannot be met by photon-based therapy.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. RAD-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

RADIATION TECHNIQUES*

Palliative 3D Conformal RT, IMRT, and SBRT • Palliative radiation should be considered in the advanced cancer setting when curative-intent treatment is not appropriate. • No general consensus exists for appropriate palliative RT regimens in head and neck cancer. For those who are either medically unsuitable for standard RT or who have widely metastatic disease, palliative RT should be considered for relief or prevention of locoregional symptoms if the RT toxicities are acceptable. RT regimens should be tailored individually; severe RT toxicities should be avoided when treatment is for palliation. Recommended RT regimens include: 50 Gy in 20 fractions;13 37.5 Gy in 15 fractions (if well tolerated, consider adding 5 additional fractions to 50 Gy); 30 Gy in 10 fractions; 30 Gy in 5 fractions:** give 2 fractions/wk with ≥3 days between the 2 treatments; and14 44.4 Gy in 12 fractions, in 3 cycles (for each cycle, give 2 fractions six hours apart for 2 days in a row, and treatments must exclude the spinal cord after second cycle).15,16 Reassessment should be done at 1- to 3-week intervals. • While the use of shorter treatment courses is encouraged, the dose tolerance of the spinal cord and neural structures must be evaluated carefully in light of fraction size. • Carefully evaluate the patient’s performance, treatment tolerance, tumor response, and/or any systemic progression. Other palliative/ supportive care measures include analgesics, nutrition support, targeted therapy, or chemotherapy, if indicated (see the NCCN Guidelines for Supportive Care).

Reirradiation with 3D Conformal RT, SBRT, PBT, or IMRT17-28 • It is strongly recommended that patients be evaluated by a multidisciplinary team at a high-volume head and neck center before reirradiation. • Prior radiotherapy should be more than 6 months from the appearance of new disease. • Before reirradiation, the patient should have a reasonable ECOG performance status of 0-1. • The treatment team must be able to develop a reirradiation treatment plan that limits the cumulative dose of radiation to CNS tissues based on volume and the time interval between prior radiotherapy and anticipated retreatment. • Radiation volumes should include known disease only. There is no need to treat prophylactic regions. • When using SBRT techniques selection of patients who do not have circumferential carotid involvement is advised. • For 3D conformal RT and IMRT: Standard dosing is 59.4–60 Gy at 1.8–2 Gy/fraction. Hyperfractionated schedule is 60 Gy at 1.2–1.5 Gy/fraction. • Current SBRT schedules being used or investigated are in the range of 30–44 Gy using 5 fractions. • Research opportunities for reirradiation should be strongly considered in patients with unresectable head and neck cancer.

*For additional resources regarding the technical details of radiation, see the American College of Radiology Guidelines: http://www.acr.org/Quality-Safety/Standards-Guidelines/Practice-Guidelines-by-Modality/Radiation-Oncology. **For end-stage disease, patients can be given more hypofractionated schedules because of the very limited prognosis. Continued

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. RAD-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 3 OF 5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

RADIATION TECHNIQUES (References) 1Dogan N, King S, Emami B, et al. Assessment of different IMRT boost delivery 13Stevens CM, Huang SH, Fung S, et al. Retrospective study of palliative methods on target coverage and normal-tissue sparing. Int J Radiat Oncol Biol radiotherapy in newly diagnosed head and neck carcinoma. Int J Radiat Oncol Phys 2003;57(5):1480-1491. Biol Phys 2011; 81:958-963. 2Lee NY, de Arruda FF, Puri DR, et al. A comparison of intensity-modulated 14Porceddu SV, Rosser B, Burmeister BH, et al. Hypofractioned radiotherapy for the radiation therapy and concomitant boost radiotherapy in the setting of concurrent palliation of advanced head and neck cancer in patients unsuitable for curative chemotherapy for locally advanced oropharyngeal carcinoma. Int J Radiat Oncol treatment-“Hypo Trial”. Radiother Oncol 2007;85:456-462. Biol Phys 2006;66(4):966-974. 15Paris KJ, Spanos WJ Jr, Lindberg RD, et al. Phase I-II study of multiple daily 3Lee NY, O'Meara W, Chan K, et al. Concurrent chemotherapy and intensity- fractions for palliation of advanced head and neck malignancies. Int J Radiat modulated radiotherapy for locoregionally advanced laryngeal and Oncol Biol Phys 1993;25:657-660. hypopharyngeal cancers. Int J Radiat Oncol Biol Phys 2007;69(2):459-468. 16Corry J, Peters LJ, Costa ID, et al. The ‘QUAD SHOT’--a phase II study of palliative 4Wu Q, Mohan R, Morris M, et al. Simultaneous integrated boost intensity- radiotherapy for incurable head and neck cancer. Radiother Oncol 2005;77:137-142. modulated radiotherapy for locally advanced head-and-neck squamous cell 17Strojan P1, Corry J, Eisbruch A, et al. Recurrent and second primary squamous carcinomas. I: dosimetric results. Int J Radiat Oncol Biol Phys 2003;56:573-585. cell carcinoma of the head and neck: when and how to reirradiate. Head Neck 5Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per 2015;37:134-150. week of conventional radiotherapy of squamous-cell carcinoma of head and neck: 18Mendenhall WM, Mendenhall CM, Malyapa RS, et al. Re-irradiation of head and DAHANCA 6 and 7 randomised controlled trial. Lancet 2003;362(9388):933-940. neck carcinoma. Am J Clin Oncol 2008;31:393-398. 6Schoenfeld GO, Amdur RJ, Morris CG, et al. Patterns of failure and toxicity after 19Riaz N, Hong JC, Sherman EJ, et al. A nomogram to predict loco-regional control intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol after re-irradiation for head and neck cancer. Radiother Oncol 2014;111:382-387. Biol Phys 2008;71(2):377-385. Epub 2007 Dec 31. 20Shikama N, Kumazaki Y, Tsukamoto N, et al. Validation of nomogram-based 7Wolden SL, Chen WC, Pfister DG, et al. Intensity-modulated radiation therapy prediction of survival probability after salvage re-irradiation of head and neck cancer. (IMRT) for nasopharynx cancer: update of the Memorial Sloan-Kettering Jpn J Clin Oncol 2013;43:154-160. experience. Int J Radiat Oncol Biol Phys 2006;64(1):57-62. 21Nieder C, Grosu AL, Andratschke NH, et al. Update of human spinal cord 8Wu Q, Manning M, Schmidt-Ullrich R, Mohan R. The potential for sparing of reirradiation tolerance based on additional data from 38 patients. Int J Radiat Oncol parotids and escalation of biologically effective dose with intensity-modulated Biol Phys 2006;66:1446-1449. radiation treatments of head and neck cancers: a treatment design study. Int J 22Chen CC, Lee CC, Mah D, et al. Dose sparing of brainstem and spinal cord for re- Radiat Oncol Biol Phys 2000;46(1):195-205. irradiating recurrent head and neck cancer with intensity-modulated radiotherapy. 9Salama JK, Haddad RI, Kies MS, et al. Clinical practice recommendations Med Dosim 2011;36:21-27. for radiotherapy planning following induction chemotherapy in locoregionally 23Stoiber EM, Schwarz M, Debus J, et al. Regional cumulative maximum dose to the advanced head and neck cancer. Int J Radiat Oncol Biol Phys 2009 75(3):725- spinal cord in head-and-neck cancer: considerations for re-irradiation. Radiother 733. Oncol 2013;106:96-100. 10Hartford AC, Palisca MG, Eichler TJ, et al. American Society for Therapeutic 24Tanvetyanon T, Padhya T, McCaffrey J, et al. Prognostic factors for survival after Radiology and Oncology (ASTRO) and American College of Radiology (ACR) salvage reirradiation of head and neck cancer. J Clin Oncol 2009;27:1983-1991. practice guidelines for intensity-modulated radiation therapy (IMRT). Int J Radiat 25Eekers DB, Roelofs E, Jelen U, et al. Benefit of particle therapy in re-irradiation Oncol Biol Phys 2009;73(1):9-14. of head and neck patients. Results of a multicentric in silico ROCOCO trial. 11IMRT Documentation Working Group, Holmes T, Das R, Low D, et al. Radiother Oncol 2016. American Society of Radiation Oncology recommendations for documenting 26Lee JY, Suresh K, Nguyen R, et al. Predictors of severe long-term toxicity after re- intensity-modulated radiation therapy treatments. Int J Radiat Oncol Biol Phys irradiation for head and neck cancer. Oral Oncol 2016;60:32-40. 2009;74:1311-1318. 27Vargo JA, Kubicek GJ, Ferris RL, et al. Adjuvant stereotactic body radiotherapy+/- 12International Commission on Radiation Units and Measurements. ICRU Report cetuximab following salvage surgery in previously irradiated head and neck 83: Prescribing, Recording, and Reporting Intensity-Modulated Photon-Beam cancer. Laryngoscope 2014;124:1579-1584. Therapy (IMRT). ICRU Report 83: 2010. 28Prawira A, Oosting S, Chen T, et al. Systemic therapies for recurrent/metastatic nasopharyngeal carcinoma (RM NPC). J Clin Oncol 2016;34(Suppl):Abstract 6031.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. RAD-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 4 OF 5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

RADIATION TECHNIQUES (References) 29Holliday EB, Garden A, Rosenthal D, et al. Proton therapy reduces treatment- 40Romesser P, Cahlon O, Scher E, et al. Proton beam radiation therapy results in related toxicities for patients with nasopharyngeal cancer: A case-match control significantly reduced toxicity compared with intensity-modulated radiation therapy study of intensity-modulated proton therapy and intensity-modulated photon for head and neck tumors that require ipsilateral radiation. Radiother Oncol 2016; therapy. Int J Part Ther 2015;2(1):1-10. 118(2):286-292. 30Holliday EB and Frank SJ. Proton therapy for nasopharyngeal carcinoma. Chin 41Romesser PB, Cahlon O, Scher ED, et al. Proton beam reirradiation for recurrent Clin Oncol 2016; 5(2):25. head and neck cancer: multi-institutional report on feasibility and early outcomes. 31McDonald MW, Liu Y, Moore MG, et al. Acute toxicity in comprehensive head and Int J Radiat Oncol Biol Phys 2016;95(1):386-395. neck radiation for nasopharynx and paranasal sinus cancers: cohort comparison 42Phan J, Sio TT, Nguyen TP, et al. Reirradiation of head and neck cancers with of 3D conformal proton therapy and intensity modulated radiation therapy. Radiat proton therapy: outcomes and analyses. Int J Radiat Oncol Biol Phys 2016;96 Oncol 2016;11:32. (1):30-41. 32 Patel SH, Wang Z, Wong WW, et al. Charged particle therapy versus photon 43Simone CB II, Ly D, Dan TD, et al. Comparison of intensity-modulated radiotherapy, therapy for paranasal sinus and nasal cavity malignant disease: a systematic review and meta-analysis. Lancet Oncol 2014;15:1027-1038. adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer. Radiother Oncol 33Russo AL, Adams JA, Weyman EA, et al. Long-term outcomes after proton beam 2011;101:376-382. therapy for sinonasal squamous cell carcinoma. Int J Radiation Oncol Biol Phys 44 95(1):368-376. van de Water TA, Bijl HP, Schilstra C, et al. The potential benefit of radiotherapy with 34 protons in head and neck cancer with respect to normal tissue sparing: a systematic Dagan R, Bryant C, Li Z, et al. Outcomes of sinonasal cancer treated with proton review of literature. Oncologist 2011;16:366-377. therapy. Int J Radiat Oncol Biol Phys 2016;95(1):377-385. 45 35 van der Laan HP, van de Water TA, van Herpt HE, et al. The potential of intensity- Bhattasali O, Holliday E, Kies MS, et al. Definitive proton radiation therapy and modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of concurrent cisplatin for unresectable head and neck adenoid cystic carcinoma: head and neck cancer: A planning comparative study. Acta Oncol 2013;52:561-569. A series of 9 cases and a critical review of the literature. Head Neck 2016;38: E1472-1480. 46Widesott L, Pierelli A, Fioino C, et al. Intensity-modulated proton therapy versus 36Holliday EB, Bhattasali O, Kies MS, et al. Effective use of intensity-modulated helical tomotherapy in nasopharynx cancer: planning comparison and NTCP proton therapy for robust delivery of post-operative radiation for head and neck evaluation. Int J Radiat Oncol Biol Phys 2008;72:589-596. adenoid cystic carcinoma. Int J Part Ther 2016;533-543. 47Kandula S, Zhu X, Garden AS, et al. Spot-scanning beam proton therapy vs 37El-Sawy T, Frank SJ, Hanna E, et al. Multidisciplinary management of lacrimal intensity-modulated radiation therapy for ipsilateral head and neck malignancies: a sac/nasolacrimal duct carcinomas. Ophthal Plast Reconstr Surg 2013; 29:454- treatment planning comparison. Med Dosim 2013;38:390-394. 457. 48Jakobi A, Stutzer K, Bandurska-Lugue A, et al. NTCP reduction for advanced head 38Bui M, Frank SJ, Nasser QJ, et al. Multidisciplinary management of primary and neck cancer patients using proton therapy for complete or sequential boost adenoid cystic carcinoma of the eyelid with perineural invasion. Ophthal Plast treatment versus photon therapy. Acta Oncol 2015;54:1658-1664. Reconstr Surg 2013; 29:e143-146. 49van de Water TA, Lomax AJ, Bijl HP, et al. Potential benefits of scanned intensity- 39Holliday EB, Esmaeli B, Pinkckard J, et al. A multidisciplinary orbit-sparing modulated proton therapy versus advanced photon therapy with regard to sparing treatment approach that includes proton therapy for epithelial tumors of the orbit of the salivary glands in oropharyngeal cancer. Int J Radiat Oncol Biol Phys 2011; and ocular adnexa. Int J Radiation Oncol Biol Phys 2016;95(1):344-352. 79:1216-1224.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. RAD-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 5 OF 5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SYSTEMIC THERAPY The choice of systemic therapy should be individualized based on patient characteristics (PS, goals of therapy). • The preferred chemoradiotherapy approach for fit patients with locally advanced disease remains concurrent cisplatin and radiotherapy. • Cisplatin-based induction chemotherapy can be used, followed by radiation-based locoregional treatment (ie, sequential chemoRT). However, an improvement in overall survival with the incorporation of induction chemotherapy compared to proceeding directly to state-of- the-art concurrent chemoRT (cisplatin preferred, category 1) has not been established in randomized studies. • Cisplatin-based induction chemotherapy followed by high-dose, every-3-week cisplatin chemoradiotherapy is not recommended due to toxicity concerns.1,2 • After induction chemotherapy, multiple options can be used for the radiation-based portion of therapy. Radiotherapy alone versus radiotherapy plus weekly carboplatin or cetuximab are among the options.

Squamous Cell Cancers Lip, Oral Cavity, Oropharynx, Hypopharynx, Glottic Larynx, Lip, Oral Cavity, Oropharynx, Hypopharynx, Glottic Larynx, Supraglottic Larynx, Ethmoid Sinus, Maxillary Sinus, Occult Supraglottic Larynx, Ethmoid Sinus, Maxillary Sinus, Occult Primary: Primary: • Primary systemic therapy + concurrent RT • Induction*/Sequential chemotherapy High-dose cisplatin3,4 (preferred) (category 1) Docetaxel/cisplatin/5-FU23-25 (category 1 if induction is chosen) Cetuximab5 (category 1 for oropharynx, hypopharynx, or larynx; Paclitaxel/cisplatin/infusional 5-FU26 category 2B for lip, oral cavity, ethmoid sinus, maxillary sinus, occult Following induction, agents used with concurrent primary) chemoradiation typically include weekly carboplatin, weekly Carboplatin/infusional 5-FU (category 1)6,7 cisplatin (category 2B), or weekly cetuximab1,27,28 8 5-FU/hydroxyurea Nasopharynx: 8 Cisplatin/paclitaxel • Induction/Sequential chemotherapy 9 Cisplatin/infusional 5-FU Docetaxel/cisplatin/5-FU29 10 Carboplatin/paclitaxel (category 2B) Docetaxel/cisplatin (category 2B)30 2 11,12 Weekly cisplatin 40 mg/m (category 2B) Cisplatin/5-FU24 • Postoperative chemoradiation Cisplatin/epirubicin/paclitaxel 13-18 Cisplatin (category 1 for high-risk** non-oropharyngeal cancers) Following induction, agents to be used with concurrent Nasopharynx: chemoradiation typically include weekly cisplatin20 or • Chemoradiation followed by adjuvant chemotherapy carboplatin27 Cisplatin + RT followed by cisplatin/5-FU19-20 or carboplatin/5-FU21 (category 2B for carboplatin/5-FU) • Cisplatin + RT without adjuvant chemotherapy (category 2B)22

*The categories of evidence and consensus for induction therapy vary depending on site. (See disease-specific site in the Head and Neck Table of Contents) **Adverse features: extranodal extension and/or positive margins. Continued

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. CHEM-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SYSTEMIC THERAPY • The choice of systemic therapy should be individualized based on patient characteristics (PS, goals of therapy). • Unless otherwise specified, regimens listed below can be used for either nasopharyngeal or non-nasopharyngeal cancer.

Recurrent, Unresectable, or Metastatic (with no surgery or RT option) • First-Line Combination Therapy Options: Cisplatin or carboplatin/5-FU/cetuximab30 (non-nasopharyngeal) (category 1) Cisplatin or carboplatin/docetaxel31 or paclitaxel32 Cisplatin/cetuximab33 (non-nasopharyngeal) Cisplatin/5-FU32,34 Cisplatin or carboplatin/docetaxel/cetuximab35 (non-nasopharyngeal) Cisplatin or carboplatin/paclitaxel/cetuximab36,37 (non-nasopharyngeal) Cisplatin/gemcitabine39,40 (category 1) (nasopharyngeal) Carboplatin/cetuximab41 (nasopharyngeal) • First-Line Single-Agent Options: Cisplatin33,42 Carboplatin43 Paclitaxel44 Docetaxel45,46 5-FU42 Methotrexate47,48 Cetuximab49 (non-nasopharyngeal) Gemcitabine50 (nasopharyngeal) Capecitabine51 • Second-Line Therapy or Subsequent Therapy Options: Combination therapy options listed above Single-agent options listed above Nivolumab52 (non-nasopharyngeal, if disease progression on or after platinum-containing chemotherapy) (category 1) Pembrolizumab53-55 ◊◊Non-nasopharyngeal: if disease progression on or after platinum-containing chemotherapy ◊◊Nasopharyngeal: if previously treated, PD-L1-positive recurrent or metastatic disease (category 2B) Afatinib56 (non-nasopharyngeal, if disease progression on or after platinum-containing chemotherapy) (category 2B)

See References on CHEM-A 3 of 5

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. CHEM-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SYSTEMIC THERAPY (References) 1Lefebvre JL, Pointreau Y, Rolland F, et al. Induction chemotherapy followed 11Beckmann GK, Hoppe F, Pfreundner L, et al. Hyperfractionated accelerated by either chemoradiotherapy or bioradiotherapy for larynx preservation: the radiotherapy in combination with weekly cisplatin for locally advanced head TREMPLIN randomized phase II study. J Clin Oncol 2013;31:853-859. and neck cancer. Head Neck 2005;27:36-43. 2Adelstein DJ, Moon J, Hanna E, et al. Docetaxel, cisplatin, and fluorouracil 12Medina JA, Rueda A, de Pasos AS, et al. A phase II study of concomitant induction chemotherapy followed by accelerated fractionation/concomitant boost boost radiation plus concurrent weekly cisplatin for locally advanced radiation and concurrent cisplatin in patients with advanced squamous cell head unresectable head and neck carcinomas. Radiother Oncol 2006;79:34-38. and neck cancer: A Southwest Oncology Group phase II trial (S0216). Head 13Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent Neck. 2010;32:221-228. radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the 3Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a head and neck. N Engl J Med 2004;350:1937-1944. comparison of three nonsurgical treatment strategies to preserve the larynx in 14Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or patients with locally advanced larynx cancer. J Clin Oncol 2013;31:845-852. without concomitant chemotherapy for locally advanced head and neck 4Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of cancer. N Engl J Med 2004;350:1945-1952. standard radiation therapy and two schedules of concurrent chemoradiotherapy 15Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced in patients with unresectable squamous cell head and neck cancer. J Clin Oncol head and neck cancers: A comparative analysis of concurrent postoperative 2003;21(1):92-98. radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 5Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for 9501). Head Neck 2005;27:843-850. locoregionally advanced head and neck cancer: 5-year survival data from a 16Bachaud JM, Cohen-Jonathan E, Alzieu C, et al. Combined postoperative phase 3 randomised trial, and relation between cetuximab-induced rash and radiotherapy and weekly cisplatin infusion for locally advanced head and neck survival. Lancet Oncol 2010;11:21-28. carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys 6Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head 1996 Dec 1;36:999-1004. and Neck Oncology and Radiotherapy Group randomized trial comparing 17Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/ radiotherapy alone with concomitant radiochemotherapy in advanced-stage intergroup phase III trial: postoperative concurrent radiation therapy and oropharynx carcinoma. J Clin Oncol 2004;22:69-76. chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int 7Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus J Radiat Oncol Biol Phys 2012;84:1198-1205. acceleration of radiotherapy with or without concomitant chemotherapy in locally 18Noronha V, Joshi A, Patil VM, et al. Once-a-week versus once-every-3-weeks advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 cisplatin chemoradiation for locally advanced head and neck cancer: a phase randomised trial. Lancet Oncol 2012;13:145-153. III randomized noninferiority trial. J Clin Oncol 2017:Jco2017749457. 8Garden AS, Harris J, Vokes EE, et al. Preliminary results of Radiation Therapy 19Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus Oncology Group 97-03: A randomized phase II trial of concurrent radiation and radiotherapy in patients with advanced nasopharyngeal cancer: phase III chemotherapy for advanced squamous cell carcinomas of the head and neck. J randomized Intergroup study 0099. J Clin Oncol 1998;16:1310-1317. Clin Oncol 2004;22:2856-2864. 20Chan AT, Leung SF, Ngan RK, et al. Overall survival after concurrent 9Taylor S, Murthy A, Vannetzel J, et al. Randomized comparison of neoadjuvant cisplatin-radiotherapy compared with radiotherapy alone in locoregionally cisplatin and fluorouracil infusion followed by radiation versus concomitant advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2005;97:536-539. treatment in advanced head and neck cancer. J Clin Oncol 1994;12:385-395. 21Dechaphunkul T, Pruegsanusak K, Sangthawan D, et al. Concurrent 10Suntharalingam M, Haas ML, Conley BA, et al. The use of carboplatin and chemoradiotherapy with carboplatin followed by carboplatin and 5- fluorouracil paclitaxel with daily radiotherapy in patients with locally advanced squamous cell in locally advanced nasopharyngeal carcinoma. Head Neck Oncol 2011;3:30. carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 2000;47:49-56.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. CHEM-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 3 OF 5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SYSTEMIC THERAPY (References) 22Chen L, Hu CS, Chen XZ, et al. Concurrent chemoradiotherapy plus adjuvant 33Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of chemotherapy versus concurrent chemoradiotherapy alone in patients with cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre and neck cancer (E1395): An Intergroup Trial of the Eastern Cooperative randomised controlled trial. Lancet Oncol 2012;13:163-171. Oncology Group. J Clin Oncol 2005;23:3562-3567. 23Vermorken JB, Remenar E, van Herpen C, et al; EORTC 24971/TAX 323 Study 34Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial Group. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck of cisplatin plus placebo versus cisplatin plus cetuximab in metastatic/ cancer. N Engl J Med 2007;357(17):1695-1704. recurrent head and neck cancer: An Eastern Cooperative Oncology Group 24Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or Study. J Clin Oncol 2005;23:8646-8654. with docetaxel in head and neck cancer. N Engl J Med 2007;357(17):1705-1715. 35Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison 25Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction of cisplatin plus flurouracil and carboplatin plus fluorouracil versus chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx methotrexate in advanced squamous cell carcinoma of the head and neck: preservation. J Natl Cancer Inst 2009;101:498-506. A Southwest Oncology Group Study. J Clin Oncol 1992;10:1245-1251. 26Hitt R, López-Pousa A, Martínez-Trufero J, et al. Phase III study comparing 36Guigay J, Fayette J, Dillies A-F, et al. Cetuximab, docetaxel, and cisplatin cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction (TPEx) as first-line treatment in patients with recurrent or metastatic (R/M) chemotherapy followed by chemoradiotherapy in locally advanced head and neck squamous cell carcinoma of the head and neck (SCCHN): Final results cancer. J Clin Oncol 2005;23:8636-8645. of phase II trial GORTEC 2008-03 [abstract]. J Clin Oncol 2012;30(Suppl 27Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, et al. Chemoradiation 15):Abstract 5505. comparing cisplatin versus carboplatin in locally advanced nasopharyngeal 37Price KA, Cohen EE. Current treatment options for metastatic head and cancer: Randomised, non-inferiority, open trial. Eur J Cancer 2007;43:1399-1406. neck cancer. Curr Treat Options Oncol 2012;13:35-46. 28Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy followed 38Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus epidermal growth factor receptor antibody cetuximab and cisplatin for concurrent chemoradiotherapy alone in locally advanced head and neck cancer recurrent and refractory squamous cell carcinoma of the head and neck. J (PARADIGM): a randomised phase 3 trial. Lancet Oncol 2013;14:257-264. Clin Oncol 2005;23:5578-5587. 29Bae WK, Hwang JE, Shim HJ, et al. Phase II study of docetaxel, cisplatin and 39Jin Y, Cai XY, Shi YX, et al. Comparison of five cisplatin-based regimens 5FU induction chemotherapy followed by chemoradiotherapy in locoregionally frequently used as the first-line protocols in metastatic nasopharyngeal advanced npc. Cancer Chem other Pharmacol 2010; 65:589-595. carcinoma. J Cancer Res Clin Oncol 2012 Oct;138(10):1717-25. 30Hui EP, Ma BB, Leung SF, et al. Randomized phase II trial of concurrent 40Zhang L, Huang Y, Hong S, et al. Gemcitabine plus cisplatin versus cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal advanced nasopharyngeal carcinoma. J Clin Oncol 2009;27:242-249. carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet 31Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus 2016;388:1883-1892. cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-1127. 41Chan AT, Hsu MM, Goh BC, et al. Multicenter, phase II study of cetuximab 32Samlowski WE, Moon J, Kuebler JP, et al. Evaluation of the combination of in combination with carboplatin in patients with recurrent or metastatic docetaxel/carboplatin in patients with metastatic or recurrent squamous cell nasopharyngeal carcinoma. J Clin Oncol 2005;23:3568-3576. carcinoma of the head and neck (SCCHN): a Southwest Oncology Group Phase II study. Cancer Invest 2007;25:182-188.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. CHEM-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 4 OF 5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF SYSTEMIC THERAPY (References) 42Jacobs C, Lyman G, Velez-García E, et al. A phase III randomized study 51Martinez-Trufero J, Isla D, Adansa JC, et al. Phase II study of capecitabine comparing cisplatin and fluorouracil as single agents and in combination as palliative treatment for patients with recurrent and metastatic squamous for advanced squamous cell carcinoma of the head and neck J Clin Oncol head and neck cancer after previous platinum-based treatment. Br J Cancer 1992;10:257-263. 2010;102:1687-1691. 43Al-Sarraf M, Metch B, Kish J, et al. Platinum analogs in recurrent and 52Ferris R, Blumenschein G, Fayette J, et al. Nivolumab for recurrent squamous- advanced head and neck cancer: a Southwest Oncology Group and Wayne cell carcinoma of the head and neck. N Engl J Med 2016;375:1856-1867. State University Study.Cancer Treat Rep 1987;71:732-736. 53Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of 44Grau JJ, Caballero M, Verger E, et al. Weekly paclitaxel for platin-resistant pembrolizumab for treatment of recurrent or metastatic squamous cell stage IV head and neck cancer patients. Acta Otolaryngol 2009;129:1294- carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, 1299. phase 1b trial. Lancet Oncol 2016;17:956-965. 45Catimel G, Verweij J, Mattijssen V, et al. Docetaxel (Taxotere): an active drug 54Chow LQ, Haddad R, Gupta S, et al. Antitumor activity of pembrolizumab in for the treatment of patients with advanced squamous cell carcinoma of the biomarker-unselected patients with recurrent and/or metastatic head and neck head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994;5:533- squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion 537. cohort. J Clin Oncol 2016;34:3838-3845. 46Guardiola E, Peyrade F, Chaigneau L, et al. Results of a randomised phase II 55Hsu C, Lee SH, Ejadi S, et al. Safety and antitumor activity of pembrolizumab study comparing docetaxel with methotrexate in patients with recurrent head in patients with programmed death-ligand 1-positive nasopharyngeal carcinoma: and neck cancer. Eur J Cancer 2004;40:2071-2076. results of the KEYNOTE-028 study. J Clin Oncol 2017;35:4050-4056. 47Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared 56Machiels JP, Haddad RI, Fayette J, et al. Afatinib versus methotrexate as with intravenous methotrexate for recurrent squamous cell carcinoma of the second-line treatment in patients with recurrent or metastatic squamous-cell head and neck [corrected]. J Clin Oncol 2009;27:1864-1871. carcinoma of the head and neck progressing on or after platinum-based therapy 48Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate 2015;16:583-594. in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992;10:1245-1251. 49Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25:2171-2177. 50Zhang L, Zhang Y, Huang PY, et al. Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy. Cancer Chemother Pharmacol 2008;61:33-38.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. CHEM-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 5 OF 5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF NUTRITION: MANAGEMENT AND SUPPORTIVE CARE1-3 Most head and neck cancer patients lose weight and are nutritionally compromised as a result of their disease, health behaviors, and treatment-related toxicities. Nutritional management is very important in head and neck cancer patients to improve outcomes and to minimize significant temporary or permanent treatment-related complications (eg, severe weight loss).A registered dietitian and a speech language/ swallowing therapist should be part of the multidisciplinary team for treating patients with head and neck cancer throughout the continuum of care. Assessment and Management • Nutrition Close monitoring of nutritional status is recommended in patients who have: 1) significant weight loss (5% weight loss over prior 1 month, or 10% weight loss over 6 months); and/or 2) difficulty swallowing because of pain or tumor involvement prior to treatment. All patients should be evaluated for nutritional risks and should receive nutrition counseling by a registered dietitian and/or indicated treatment with various nutrition interventions, such as feeding tubes (eg, nasogastric [NG] tubes, percutaneous endoscopic gastrostomy [PEG] tubes) or intravenous nutrition support (but only if enteral support is not feasible). Pre- and post-treatment functional evaluation including nutritional status should be undertaken using subjective and objective assessment tools. All patients should receive dietary counseling with the initiation of treatment, especially with radiotherapy-based treatments. Regular follow-up with the registered dietitian should continue at least until the patient has achieved a nutritionally stable baseline following treatment. For some patients with chronic nutritional challenges, this follow-up should be ongoing. • Speech and Swallowing A formal speech and swallowing evaluation at baseline is recommended for either: 1) patients with speech and/or swallowing dysfunction; or 2) patients whose treatment is likely to affect speech and/or swallowing. Patients with ongoing abnormal function should be seen regularly by speech-language pathologists. Dysphagia and swallowing function can be measured by clinical swallowing assessments or by videofluoroscopic swallowing studies. Patient evaluations should also include assessment for any changes in speech and communication; changes in taste; and assessment for xerostomia, pain, and trismus. Follow- up with the speech-language pathologist should continue at least until the patient has achieved a stable baseline following treatment. For some patients with chronic speech and swallowing challenges, this follow-up may need to be indefinite. • Pain 4 5 Assess pain from oral mucositis and prescribe gabapentin or doxepin as clinically indicated. Continued 1Ehrsson YT, Langius-Eklöf A, Laurell G. Nutritional surveillance and weight loss in head and neck cancer patients. Support Care Cancer 2012;20:757-765. 4Bar Ad V, Weinstein G, Dutta PR, et al. Gabapentin for the treatment of 2Locher JL, Bonner JA, Carroll WR, et al. Prophylactic percutaneous endoscopic pain syndrome related to radiation-induced mucositis in patients with head gastrostomy tube placement in treatment of head and neck cancer: a comprehensive and neck cancer treated with concurrent chemoradiotherapy. Cancer review and call for evidence-based medicine. JPEN J Parenter Enteral Nutr 2010;116:4206-4213. 2011;35:365-374. 5Leenstra JL, Miller RC, Qin R, et al. Doxepin rinse versus placebo in the 3Langius JA, van Dijk AM, Doornaert P, et al. More than 10% weight loss in head and treatment of acute oral mucositis pain in patients receiving head and neck neck cancer patients during radiotherapy is independently associated with deterioration radiotherapy with or without chemotherapy: a phase III, randomized, double- in quality of life. Nutr Cancer 2013;65:76-83. blind trial (NCCTG-N09C6 [Alliance]). J Clin Oncol 2014;32:1571-1577.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NUTR-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF NUTRITION: MANAGEMENT AND SUPPORTIVE CARE1-3 Use of Alternative Routes for Nutrition (NG and PEG tubes) • The panel does not recommend prophylactic PEG or NG tube placement in patients with very good PS and without significant pretreatment weight loss, significant airway obstruction, or severe dysphagia. However, these patients will need encouragement to monitor their caloric intake and to assess for changes in body weight during treatment. They also may need temporary tube feeding intervention during and/or after treatment.

• Prophylactic feeding tube placement should be strongly considered for patients with: Severe weight loss prior to treatment, 5% weight loss over prior 1 month, or 10% weight loss over 6 months; Ongoing dehydration or dysphagia, anorexia, or pain interfering with the ability to eat/drink adequately; Significant comorbidities that may be aggravated by poor tolerance of dehydration, lack of caloric intake, or difficulty swallowing necessary medications; Severe aspiration; or mild aspiration in elderly patients or in patients who have compromised cardiopulmonary function; or Patients for whom long-term swallowing disorders are likely, including those anticipated to receive large fields of high-dose radiation to the mucosa and adjacent connective tissues. However, consideration of other risk factors for swallowing dysfunction must be taken into account as well.

• To maintain swallowing function during and following treatment (eg, radiation), patients who may have feeding tube placement should be encouraged to intake orally if they can swallow without aspiration or any other compromises. Alterations in swallowing function can occur long after treatment (especially after radiation-based treatment) and should be monitored for the lifetime of the patient.

1Ehrsson YT, Langius-Eklöf A, Laurell G. Nutritional surveillance and weight loss in head and neck cancer patients. Support Care Cancer 2012;20:757-765. 2Locher JL, Bonner JA, Carroll WR, et al. Prophylactic percutaneous endoscopic gastrostomy tube placement in treatment of head and neck cancer: a comprehensive review and call for evidence-based medicine. JPEN J Parenter Enteral Nutr 2011;35:365-374. 3Langius JA, van Dijk AM, Doornaert P, et al. More than 10% weight loss in head and neck cancer patients during radiotherapy is independently associated with deterioration in quality of life. Nutr Cancer 2013;65:76-83.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. NUTR-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF DENTAL EVALUATION AND MANAGEMENT Radiation therapy to the head and neck causes xerostomia and salivary gland dysfunction, which dramatically increases the risk of dental caries and its sequelae, including dentoalveolar infection and osteoradionecrosis. Radiation therapy also affects the dental hard tissues, which increases their susceptibility to demineralization1 within the presence of xerostomia, microbial changes following RT, and changes to a more cariogenic diet. IMRT and salivary gland-sparing techniques are associated with dose-dependent recovery of salivary function over time2 and with reduced risk for dental caries long term for some patients.3 Radiation-related caries and other dental hard tissue changes can appear within the first 3 months following RT.4,5 Goals of Pre-RT Dental/Oral Evaluation: 1. Patient education, both oral and written, regarding oral and dental complications of RT and need for compliance with preventive protocols. • Effect on salivary glands Dry mouth strategies ◊◊Increased hydration ◊◊Salivary substitutes (eg, calcium phosphate-containing solutions; gels containing lysozyme, lactoferrin, and peroxidase) ◊◊Alcohol-free mouthwash ◊◊Salivary stimulation ––Gustatory stimulants (eg, xylitol chewing gum, sorbitol/malic acid lozenges, xylitol lozenges) ––Cholinergic agonists (pilocarpine, cevimeline)6,7 Dental caries prevention ◊◊Diet counseling ◊◊High potency topical fluoride – continue long term after therapy ––Daily 1.1% NaF gel or SNF2 gel, brush on or in custom dental trays or ––Daily 1.1% NaF dentifrice or ––Fluoride varnish application, three times per year ––Calcium phosphate artificial saliva rinse ◊◊Regular frequent dental evaluations to detect dental disease • Effect on bone in irradiated field Need for pre-RT dental evaluation and determine need for dental extractions3,8,9 ◊◊If yes, should be completed at least 2 weeks prior to start of RT ◊◊Long-term prognosis of teeth and patient motivation should be considered ◊◊Need to contact oncology team if any future extractions or surgery in irradiated field • Effect on masticatory muscles – potential for trismus4,5 Maintain range of motion ◊◊Tongue blades and gentle stretching ◊◊Custom mouth-opening devices for rehabilitation of trismus and jaw motion Continued

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. DENT-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 3 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF DENTAL EVALUATION AND MANAGEMENT

Goals of Pre-RT Dental/Oral Evaluation—(continued): 2. Examination and assessment of patient with treatment plan4 • Complete oral and head and neck examination, including radiographs of all teeth • Risk assessment for caries and periodontal disease Existing periodontal and dental conditions Radiographic evidence of periapical pathology Oral hygiene Past dental history Patient motivation and compliance • Treatment plan Eliminate potential sources of infection Extractions at least 2 weeks before start of RT Treat active dental caries, periodontal disease Silicone guards to minimize radiation backscatter, if patients have metal restorations Prescribe potent topical fluoride for daily use. Duration of use to be determined by periodic caries risk assessment over time Return visit for re-evaluation and reinforcement of preventive protocol, during last week of RT Evaluate for oral candidiasis and treat appropriately with antifungal agents

Goals of Dental Management During Cancer Therapy: 1. Manage xerostomia 2. Prevent trismus of masticatory muscles 3. Evaluate for oral candidiasis and treat as clinically indicated

Goals of Dental Management Post-Treatment: 1. Manage xerostomia 2. Prevent and minimize trismus 3. Prevent and treat dental caries 4. Prevent post-radiation osteonecrosis 5. Prevent and manage oral candidiasis 6. Consultation with treating radiation oncologist is recommended before considering implants or extraction.

Dental recall visit interval based on risk, at least once every 6 months, or more frequently for those with xerostomia, or for those with new caries lesions following radiotherapy. Continued

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. DENT-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 3 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PRINCIPLES OF DENTAL EVALUATION AND MANAGEMENT (References)

1Walker MP, Wichman B, Cheng AL, Coster J, Williams KB. Impact of radiotherapy dose on dentition breakdown in head and neck cancer patients. Pract Radiat Oncol 2011;1:142-148. 2Little M, Schipper M, Feng FY, et al. Reducing xerostomia after chemo-IMRT for head-and-neck cancer: beyond sparing the parotid glands. Int J Radiat Oncol Biol Phys 2012; 83:1007-1014. 3Studer G, Glanzmann C, Studer SP, et al. Risk-adapted dental care prior to intensity-modulated radiotherapy (IMRT). Schweiz Monatsschr Zahnmed 2011;121:216- 229. 4Murdoch-Kinch CA, Zwetchkenbaum S. Dental management of the head and neck cancer patient treated with radiation therapy. J Mich Dent Assoc 2011; 93:28-37. 5Epstein JB, Thariat J, Bensadoun RJ, et al. Oral complications of cancer and cancer therapy: from cancer treatment to survivorship. CA Cancer J Clin 2012; 62:400-422. 6Gorsky M, Epstein JB, Parry J, Epstein MS, Le ND, Silverman S, Jr. The efficacy of pilocarpine and bethanechol upon saliva production in cancer patients with hyposalivation following radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004; 97:190-195. 7Jensen SB, Pedersen AM, Vissink Aet al. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact. Support Care Cancer 2010;18:1061-1079. 8Gomez DR, Estilo CL, Wolden SLet al. Correlation of osteoradionecrosis and dental events with dosimetric parameters in intensity-modulated radiation therapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011; 81:e207-213. 9Lee IJ, Koom WS, Lee CGet al. Risk factors and dose-effect relationship for mandibular osteoradionecrosis in oral and oropharyngeal cancer patients. Int J Radiat Oncol Biol Phys 2009; 75:1084-1091.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. DENT-A Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 3 OF 3 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 1 American Joint Committee on Cancer (AJCC) TNM Staging Classification for the Oral Cavity (including mucosa of lip) (8th ed., 2017) (Nonepithelial tumors such as those of lymphoid tissue, soft tissue, bone, and cartilage, mucosal melanoma, and cutaneous squamous cell carcinoma of the vermilion lip are not included) Primary Tumor (T) Regional Lymph Nodes (N) TX Primary tumor cannot be assessed Clinical N (cN) Tis Carcinoma in situ NX Regional lymph nodes cannot be assessed T1 Tumor ≤2 cm, ≤5 mm depth of invasion (DOI) N0 No regional lymph node metastasis DOI is depth of invasion and not tumor N1 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in thickness greatest dimension ENE(–) T2 Tumor ≤2 cm, DOI >5 mm and ≤10 mm N2 Metastasis in a single ipsilateral node larger than 3 cm but not larger or tumor >2 cm but ≤4 cm, and ≤10 mm DOI than 6 cm in greatest dimension and ENE(–); or metastases in multiple T3 Tumor >4 cm or any tumor with DOI >10 mm but ipsilateral lymph nodes, none larger than 6 cm in greatest dimension ≤20 mm and ENE(–); or in bilateral or contralateral lymph nodes, none larger T4 Moderately advanced or very advanced local than 6 cm in greatest dimension, and ENE(–) disease N2a Metastasis in a single ipsilateral lymph node larger than 3 cm but not T4a Moderately advanced local disease larger than 6 cm in greatest dimension, and ENE(–) Tumor invades adjacent structures only (e.g., N2b Metastasis in multiple ipsilateral lymph nodes, none larger than 6 cm in through cortical bone of the mandible or maxilla, greatest dimension, and ENE(–) or involves the maxillary sinus or skin of the N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 face)* or extensive tumor with bilateral tongue cm in greatest dimension, and ENE(–) involvement and/or DOI > 20 mm. N3 Metastasis in a lymph node larger than 6 cm in greatest dimension and T4b Very advanced local disease ENE(−); or metastasis in any node(s) and clinically overt ENE(+) Tumor invades masticator space, pterygoid N3a Metastasis in a lymph node larger than 6 cm in greatest dimension and plates, or skull base and/or encases the internal ENE(−) carotid artery N3b Metastasis in any node(s) and clinically overt ENE(+) *Note: Superficial erosion of bone/tooth socket (alone) by a gingival Note: A designation of “U” or “L” may be used for any N category to indicate metastasis primary is not sufficient to classify a tumor as T4. above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(−) or ENE(+). Continued Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-1 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 1 — Continued American Joint Committee on Cancer (AJCC) TNM Staging Classification for the Oral Cavity (including mucosa of lip) (8th ed., 2017) (Nonepithelial tumors such as those of lymphoid tissue, soft tissue, bone, and cartilage, mucosal melanoma, and cutaneous squamous cell carcinoma of the vermilion lip are not included) Regional Lymph Nodes (N) Distant Metastasis (M) Pathological N (pN) M0 No distant metastasis NX Regional lymph nodes cannot be assessed M1 Distant metastasis N0 No regional lymph node metastasis Histologic Grade (G) N1 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(–) GX Cannot be assessed N2 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(+); or larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–);or metastases in G1 Well differentiated multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(−); or in G2 Moderately differentiated bilateral or contralateral lymph node(s), none larger than 6 cm in greatest dimension, ENE(−) G3 Poorly differentiated N2a Metastasis in single ipsilateral node 3 cm or smaller in greatest dimension, and ENE(+); or a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–) Prognostic Stage Groups N2b Metastasis in multiple ipsilateral node(s), none larger than 6 cm in greatest dimension and Stage 0 Tis N0 M0 ENE(−) Stage I T1 N0 M0 Metastasis in bilateral or contralateral lymph node(s), none larger than 6 cm in greatest N2c T2 N0 M0 dimension, and ENE(–) Stage II Stage III T1,T2 N1 M0 N3 Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(−); or in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or multiple ipsilateral, T3 N0,N1 M0 contralateral or bilateral nodes any with ENE(+); or a single contralateral node of any size and Stage IVA T1 N2 M0 ENE (+) T2 N2 M0 N3a Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(−) T3 N2 M0 N3b Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or T4a N0,N1, M0 multiple ipsilateral, contralateral or bilateral nodes any with ENE(+); or a single contralateral N2 node of any size and ENE (+) Stage IVB Any T N3 M0 Note : A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower T4b Any N M0 border of the cricoid (U) or below the lower border of the cricoid (L). Stage IVC Any T Any N M1 Similarly, clinical and pathological ENE should be recorded as ENE(−) or ENE(+).

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-2 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 2 American Joint Committee on Cancer (AJCC) TNM Staging System for the Nasopharynx (8th ed., 2017) (The following types of cancer are not included: Mucosal melanoma, lymphoma, sarcoma of the soft tissue, bone and cartilage.) Distant Metastasis (M) M0 No distant metastasis Primary Tumor (T) M1 Distant metastasis TX Primary tumor cannot be assessed Histologic Grade (G) T0 No tumor identified, but EBV-positive cervical node(s) involvement A grading system is not used for NPCs. Tis Carcinoma in situ T1 Tumor confined to the nasopharynx, or extension to oropharynx and/or nasal Anatomic Stage/Prognostic Groups cavity without parapharyngeal involvement Stage 0 Tis N0 M0 T2 Tumor with extension to parapharyngeal space, and/or adjacent soft tissue Stage I T1 N0 M0 involvement (medial pterygoid, lateral pterygoid, prevertebral muscles) Stage II T0 N1 M0 T3 Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses T1 N1 M0 T4 Tumor with intracranial extension, involvement of cranial nerves, T2 N0 M0 hypopharynx, orbit, parotid gland, and/ or extensive soft tissue infiltration T2 N1 M0 beyond the lateral surface of the lateral pterygoid muscle Stage III T0 N2 M0 T1 N2 M0 Regional Lymph Nodes (N) T2 N2 M0 NX Regional lymph nodes cannot be assessed T3 N0 M0 N0 No regional lymph node metastasis T3 N1 M0 N1 Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), 6 cm or smaller in greatest T3 N2 M0 dimension, above the caudal border of cricoid cartilage Stage IVA T4 N0 M0 N2 Bilateral metastasis in cervical lymph node(s), 6 cm or smaller in greatest T4 N1 M0 dimension, above the caudal border of cricoid cartilage T4 N2 M0 N3 Unilateral or bilateral metastasis in cervical lymph node(s), larger than 6 cm Any T N3 M0 in greatest dimension, and/or extension below the caudal border of cricoid Stage IVB Any T N3 M0 cartilage Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-3 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 3 American Joint Committee on Cancer (AJCC) TNM Staging System for the Oropharynx (p16-) and Hypopharynx (8th ed., 2017) (Not included: P16-positive (p16+) oropharyngeal cancers and nasopharyngeal cancer)

Oropharynx (p16-) Hypopharynx TX Primary tumor cannot be assessed TX Primary tumor cannot be assessed Tis Carcinoma in situ Tis Carcinoma in situ T1 Tumor 2 cm or smaller in greatest dimension T1 Tumor limited to one subsite of hypopharynx and/or 2 cm or T2 Tumor larger than 2 cm but not larger than 4 cm in greatest smaller in greatest dimension dimension T2 Tumor invades more than one subsite of hypopharynx or an T3 Tumor larger than 4 cm in greatest dimension or extension to adjacent site, or measures larger than 2 cm but not larger lingual surface of epiglottis than 4 cm in greatest dimension without fixation of hemilarynx T4 Moderately advanced or very advanced local disease T3 Tumor larger than 4 cm in greatest dimension or with fixation T4a Moderately advanced local disease of hemilarynx or extension to esophagus Tumor invades the larynx, extrinsic muscle of tongue, medial T4 Moderately advanced or very advanced local disease pterygoid, hard palate, or mandible* T4a Moderately advanced local disease T4b Very advanced local disease Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid Tumor invades lateral pterygoid muscle, pterygoid plates, gland, esophageal muscle or central compartment soft lateral nasopharynx, or skull base or encases carotid artery tissue* T4b Very advanced local disease *Note: Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does not constitute invasion of the larynx. Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures *Note: Central compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat.

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-4 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Regional Lymph Nodes (N)† Clinical N (cN) - Oropharynx (p16-) and Hypopharynx NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(−) N2 Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(−); or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(−) N2a Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(−) N2b Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(−) N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(−) N3 Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(−); or metastasis in any node(s) and clinically overt ENE(+) N3a Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(−) N3b Metastasis in any node(s) and clinically overt ENE(+)

†A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(−) or ENE(+). Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-5 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 3 — Continued American Joint Committee on Cancer (AJCC) TNM Staging System for the Oropharynx (p16-) and Hypopharynx (8th ed., 2017) (Not included: P16-positive (p16+) oropharyngeal cancers and nasopharyngeal cancer) Regional Lymph Nodes (N)†: Distant Metastasis (M) Pathological N (pN) - Oropharynx (p16-) and Hypopharynx M0 No distant metastasis NX Regional lymph nodes cannot be assessed M1 Distant metastasis N0 No regional lymph node metastasis Histologic Grade (G) N1 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest Grade Cannot be assessed dimension and ENE(−)) GX G1 Well differentiated Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest N2 G2 Moderately differentiated dimension and ENE(+); or larger than 3 cm but not larger than 6 cm in greatest G3 Poorly differentiated dimension and ENE(−); or metastases in multiple ipsilateral lymph nodes, none G4 Undifferentiated larger than 6 cm in greatest dimension and ENE(−); or in bilateral or contralateral lymph node(s), none larger than 6 cm in greatest dimension and ENE(−) N2a Metastasis in single ipsilateral node 3 cm or smaller in greatest dimension and Prognostic Stage Groups ENE(+); Stage 0 Tis N0 M0 or a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest Stage I T1 N0 M0 dimension and ENE(−) Stage II T2 N0 M0 N2b Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest Stage III T3 N0 M0 dimension and ENE(−) T1 N1 M0 N2c Metastasis in bilateral or contralateral lymph node(s), none larger than 6 cm in T2 N1 M0 greatest dimension and ENE(−) T3 N1 M0 N3 Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(−); or in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); Stage IVA T1 N2 M0 or multiple ipsilateral, contralateral or bilateral nodes, any with ENE(+); T2 N2 M0 or a single contralateral node of any size and ENE(+) T3 N2 M0 N3a Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(−) T4a N0, N1,N2 M0 N3b Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and Stage IVB T4b Any N M0 ENE(+); or multiple ipsilateral, contralateral or bilateral nodes, any with ENE(+) Any T N3 M0 or a single contralateral node of any size and ENE(+) Stage IVC Any T Any N M1 †Note: A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(−) or ENE(+).

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-6 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 4 American Joint Committee on Cancer (AJCC) TNM Staging System for HPV-Mediated (p16+) Oropharyngeal Cancer (8th ed., 2017) (Not including: P16-negative [p16-] cancers of the oropharynx) Primary Tumor (T) Prognostic Stage Groups T0 No primary identified Clinical T1 Tumor 2 cm or smaller in greatest dimension Stage I T0 N0,N1 M0 T2 Tumor larger than 2 cm but not larger than 4 cm in greatest dimension T1 N0,N1 M0 T3 Tumor larger than 4 cm in greatest dimension or extension to lingual surface of epiglottis T2 N0,N1 M0 T4 Moderately advanced local disease Stage II T0 N2 M0 Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or T1 N2 M0 mandible or beyond* T2 N2 M0 *Note: Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does not constitute invasion of the larynx. T3 N0, N1, N2 M0 Stage III T0 N3 M0 Regional Lymph Nodes (N) T1 N3 M0 Clinical N (cN) T2 N3 M0 NX Regional lymph nodes cannot be assessed T3 N3 M0 N0 No regional lymph node metastasis T4 N0, N1, N2, N3 M0 N1 One or more ipsilateral lymph nodes, none larger than 6 cm Stage IV Any T Any N M1 N2 Contralateral or bilateral lymph nodes, none larger than 6 cm N3 Lymph node(s) larger than 6 cm Pathological Pathological N (pN) Stage I T0 N0, N1 M0 NX Regional lymph nodes cannot be assessed T1 N0, N1 M0 pN0 No regional lymph node metastasis T2 N0, N1 M0 pN1 Metastasis in 4 or fewer lymph nodes Stage II T0 N2 M0 pN2 Metastasis in more than 4 lymph nodes T1 N2 M0 T2 N2 M0 Distant Metastasis (M) Stage III T3 N2 M0 M0 No distant metastasis T4 N2 M0 M1 Distant metastasis Stage IV Any T Any N M1 Histologic Grade (G) No grading system exists for HPV-mediated oropharyngeal tumors Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-7 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 5 American Joint Committee on Cancer (AJCC) TNM Staging System for the Larynx (8th ed., 2017) (Nonepithelial tumors such as those of lymphoid tissue, soft tissue, bone and cartilage, and mucosal melanoma of the lip and oral cavity are not included) Primary Tumor (T) Glottis TX Primary tumor cannot be assessed T1 Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with normal mobility Tis Carcinoma in situ T1a Tumor limited to one vocal cord T1b Tumor involves both vocal cords Supraglottis T2 Tumor extends to supraglottis and/or subglottis, and/or with impaired Tumor limited to one subsite of supraglottis with T1 vocal cord mobility normal vocal cord mobility T3 Tumor limited to the larynx with vocal cord fixation and/or invasion of T2 Tumor invades mucosa of more than one adjacent paraglottic space and/or inner cortex of the thyroid cartilage subsite of supraglottis or glottis or region outside T4 Moderately advanced or very advanced the supraglottis (eg, mucosa of base of tongue, T4a Moderately advanced local disease vallecula, medial wall of pyriform sinus) without Tumor invades through the outer cortex of the thyroid cartilage and/ fixation of the larynx or invades tissues beyond the larynx (eg, trachea, cricoid cartilage, soft T3 Tumor limited to larynx with vocal cord fixation tissues of neck including deep extrinsic muscle of the tongue, strap and/or invades any of the following: postcricoid muscles, thyroid, or esophagus) area, preepiglottic space, paraglottic space, and/or T4b Very advanced local disease; Tumor invades prevertebral space, inner cortex of thyroid cartilage encases carotid artery, or invades mediastinal structures T4 Moderately advanced or very advanced T4a Moderately advanced local disease Subglottis Tumor invades through the outer cortex of the T1 Tumor limited to the subglottis thyroid cartilage and/or invades tissues beyond the T2 Tumor extends to vocal cord(s) with normal or impaired mobility larynx (eg, trachea, soft tissues of neck including T3 Tumor limited to larynx with vocal cord fixation and/or inner cortex of deep extrinsic muscle of the tongue, strap the thyroid cartilage muscles, thyroid, or esophagus) T4 Moderately advanced or very advanced T4b Very advanced local disease T4a Moderately advanced local disease Tumor invades prevertebral space, encases Tumor invades cricoid or thyroid cartilage and/or invades tissues carotid artery, or invades mediastinal structures beyond the larynx (eg, trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus) T4b Very advanced local disease; Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-8 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 5 — Continued American Joint Committee on Cancer (AJCC) TNM Staging System for the Larynx (8th ed., 2017) (Nonepithelial tumors such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included)

Regional Lymph Nodes (N)* Clinical N (cN) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension ENE(–) N2 Metastasis in a single ipsilateral node, larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–); or metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–) N2a Metastasis in a single ipsilateral lymph node, larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–) N2b Metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–) N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–) N3 Metastasis in a lymph node, larger than 6 cm in greatest dimension and ENE(–); or metastasis in any lymph node(s) with clinically overt ENE(+) N3a Metastasis in a lymph node, larger than 6 cm in greatest dimension and ENE(−) N3b Metastasis in any lymph node(s) with clinically overt ENE(+)

*Note: A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L) Similarly, clinical and pathological ENE should be recorded as ENE(−) or ENE(+) Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-9 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Pathological N (pN) Distant Metastasis (M) NX Regional lymph nodes cannot be assessed M0 No distant metastasis N0 No regional lymph node metastasis M1 Distant metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension ENE(–) N2 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and Histologic Grade (G) ENE(+); or larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(−); GX Grade cannot be assessed or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest G1 Well differentiated dimension and ENE(−); or in bilateral or contralateral lymph node(s), none larger than 6 cm G2 Moderately differentiated in greatest dimension and ENE(−) G3 Poorly differentiated N2a Metastasis in a single ipsilateral node, 3 cm or smaller in greatest dimension and ENE(+); or metastasis in a single ipsilateral node, larger than 3 cm but not larger than 6 cm in Prognostic Stage Groups greatest dimension and ENE(−) Stage 0 Tis N0 M0 N2b Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and Stage I T1 N0 M0 ENE(−) N2c Metastasis Stage II T2 N0 M0 N2c Metastasis in bilateral or contralateral lymph node(s), none larger than 6 cm in greatest Stage III T3 N0 M0 dimension and ENE(−) T1 N1 M0 N3 Metastasis in a lymph node, larger than 6 cm in greatest dimension and ENE(−); T2 N1 M0 or metastasis in a single ipsilateral node, larger than 3 cm in greatest dimension and T3 N1 M0 ENE(+); or multiple ipsilateral, contralateral, or bilateral lymph nodes and any with ENE(+); Stage IVA T1 N2 M0 or a single contralateral node of any size and ENE(+) T2 N2 M0 N3a Metastasis in a lymph node, larger than 6 cm in greatest dimension and ENE(−) T3 N2 M0 N3b Metastasis in a single ipsilateral node, larger than 3 cm in greatest dimension and ENE(+); T4a N0, N1, N2 M0 or multiple ipsilateral, contralateral, or bilateral lymph nodes any with ENE(+); or a single Stage IVB Any T N3 M0 contralateral node of any size and ENE(+) T4b Any N M0 Stage IVC Any T Any N M1 *Note: A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L) Similarly, clinical and pathological ENE should be recorded as ENE(−) or ENE(+)

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-10 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 6 American Joint Committee on Cancer (AJCC) TNM Staging System for the Nasal Cavity and Paranasal Sinuses (8th ed., 2017) (Mucosal melanoma of the nasal cavity and paranasal sinuses are not included)

Primary Tumor (T) Nasal Cavity and Ethmoid Sinus TX Primary tumor cannot be assessed T1 Tumor restricted to any one subsite, with or without Tis Carcinoma in situ bony invasion T2 Tumor invading two subsites in a single region or extending to involve an adjacent region within Maxillary Sinus the nasoethmoidal complex, with or without bony T1 Tumor limited to maxillary sinus mucosa with no erosion or invasion destruction of bone T3 Tumor extends to invade the medial wall or floor of T2 Tumor causing bone erosion or destruction including the orbit, maxillary sinus, palate, or cribriform plate extension into the hard palate and/or middle nasal meatus, Moderately advanced or very advanced local disease except extension to posterior wall of maxillary sinus and T4 pterygoid plates T4a Moderately advanced local disease Tumor invades any of the following: anterior orbital T3 Tumor invades any of the following: bone of the posterior contents, skin of nose or cheek, minimal extension to wall of maxillary sinus, subcutaneous tissues, floor or medial anterior cranial fossa, pterygoid plates, sphenoid or wall of orbit, pterygoid fossa, ethmoid sinuses frontal sinuses T4 Moderately advanced or very advanced local disease T4b Very advanced local disease T4a Moderately advanced local disease Tumor invades any of the following: orbital apex, Tumor invades anterior orbital contents, skin of cheek, pterygoid dura, brain, middle cranial fossa, cranial nerves other plates, infratemporal fossa, cribriform plate, sphenoid or frontal than (V2), nasopharynx, or clivus sinuses T4b Very advanced local disease Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve (V2), nasopharynx, or clivus

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-11 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 6 — Continued American Joint Committee on Cancer (AJCC) TNM Staging System for the Nasal Cavity and Paranasal Sinuses (8th ed., 2017) (Mucosal melanoma of the nasal cavity and paranasal sinuses are not included)

Regional Lymph Nodes (N) Clinical N (cN) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(–) N2 Metastasis in a single ipsilateral lymph node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–); or or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–) N2a Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–) N2b Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(–) N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–) N3 Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(–); or metastasis in any node(s) with clinically overt ENE(+) N3a Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(–) N3b Metastasis in any node(s) with clinically overt ENE (ENEc)

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-12 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Regional Lymph Nodes (N) Pathological N (pN) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(–) N2 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(+); or larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(−); or in bilateral or contralateral lymph node(s), none larger than 6 cm in greatest dimension and ENE(–); N2a Metastasis in single ipsilateral node 3 cm or less in greatest dimension and ENE(+); or a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(−) N2b Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(–) N2c Metastasis in bilateral or contralateral lymph node(s), none larger than 6 cm in greatest dimension and ENE(–) N3 Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(−); or in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral or bilateral nodes, any with ENE(+); or a single contralateral node of any size and ENE(+) N3a Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(–) N3b Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral or bilateral nodes, any with ENE(+); or a single contralateral node of any size and ENE(+) Note: A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(−) or ENE(+). Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-13 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Prognostic Stage Groups Distant Metastasis (M) Stage 0 Tis N0 M0 M0 No distant metastasis (no pathologic M0; use clinical M to complete stage group) Stage I T1 N0 M0 M1 Distant metastasis Stage II T2 N0 M0 Stage III T1 N1 M0 T2 N1 M0 Histologic Grade (G) T3 N0, N1 M0 GX Grade cannot be assessed Stage IVA T1 N2 M0 G1 Well differentiated T2 N2 M0 G2 Moderately differentiated T3 N2 M0 G3 Poorly differentiated T4a N0, N1, N2 M0 Stage IVB Any T N3 M0 T4b Any N M0 Stage IVC Any T Any N M1

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-14 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 7 American Joint Committee on Cancer (AJCC) TNM Staging System for the Major Salivary Glands (8th ed., 2017) (Parotid, Submandibular, and Sublingual)

Primary Tumor (T) Regional Lymph Nodes (N) TX Primary tumor cannot be assessed Clinical N (cN) T0 No evidence of primary tumor NX Regional lymph nodes cannot be assessed Tis Carcinoma in situ N0 No regional lymph node metastasis T1 Tumor 2 cm or smaller in greatest dimension N1 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in without extraparenchymal extension* greatest dimension and ENE(-) T2 Tumor larger than 2 cm but not larger than 4 cm N2 Metastasis in a single ipsilateral lymph node, larger than 3 cm but not in greatest dimension without extraparenchymal larger than 6 cm in greatest dimension and ENE(-); or metastases in extension* multiple ipsilateral lymph node(s), none larger than 6 cm in greatest T3 Tumor larger than 4 cm and/or tumor having dimension and ENE(-); or in bilateral or contralateral lymph nodes, extraparenchymal extension* none larger than 6 cm in greatest dimension and ENE(-) T4 Moderately advanced or very advanced disease N2a Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-) T4a Moderately advanced disease N2b Metastasis in multiple ipsilateral nodes, none larger than 6 cm in Tumor invades skin, mandible, ear canal, and/ greatest dimension and ENE(-) or facial nerve N2c Metastasis in bilateral or contralateral lymph nodes, none larger than T4b Very advanced disease 6 cm in greatest dimension and ENE(-) Tumor invades skull base and/or pterygoid plates and/or encases carotid artery N3 Metastasis in a lymph node, more than 6 cm in greatest dimension and ENE(-); or metastases in any node(s) with clinically overt ENE(+) *Note: Extraparenchymal extension is clinical or macroscopic N3a Metastasis in a lymph node larger than 6 cm in greatest dimension evidence of invasion of soft tissues. Microscopic evidence alone does and ENE(−) not constitute extraparenchymal extension for classification purposes. N3b Metastasis in any node(s) with clinically overt ENE(+)

Note : A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(−) or ENE(+) Continued Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-15 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 7 — Continued American Joint Committee on Cancer (AJCC) TNM Staging System for the Major Salivary Glands (8th ed., 2017) (Parotid, Submandibular, and Sublingual) Regional Lymph Nodes (N) Distant Metastasis (M) Pathological N (pN) M0 No distant metastasis NX Regional lymph nodes cannot be assessed M1 Distant metastasis N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or less smaller in greatest Anatomic Stage/Prognostic Groups dimension and ENE(-) Stage I T1 N0 M0 N2 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(+); or larger than 3 cm but not larger than 6 cm in greatest Stage II T2 N0 M0 dimension and ENE(−); or metastases in multiple ipsilateral lymph node(s), none Stage III T3 N0 M0 larger than 6 cm in greatest dimension and ENE(−); or in bilateral or contralateral T0, T1, T2, T3 N1 M0 lymph nodes, none larger than 6 cm in greatest dimension and ENE(−) Stage IVA T0 N2 M0 N2a Metastasis in a single ipsilateral lymph node 3cm or smaller in greatest dimension and ENE(+) or a single ipsilateral node larger than 3 cm but not larger T1 N2 M0 than 6 cm in greatest dimension and ENE(-) T2 N2 M0 N2b Metastasis in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest T3 N2 M0 dimension and ENE(-) T4a N0, N1, N2 M0 N2c Metastasis in bilateral or contralateral lymph node(s), none more than 6 cm in greatest dimension and ENE(-) Stage IVB Any T N3 M0 N3 Metastasis in a lymph node, more than 6 cm in greatest dimension and ENE(-) T4b Any N M0 or in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); Stage IVC Any T Any N M1 or multiple ipsilateral, contralateral, or bilateral nodes any with ENE(+) ; or a single contralateral node of any size and ENE(+) N3a Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(−) N3b Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes any with ENE(+) ; or a single contralateral node of any size and ENE(+) Note : A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(−) or ENE(+) Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-16 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 Staging NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Table 8 American Joint Committee on Cancer (AJCC) TNM Staging System for Mucosal Melanoma of the Head and Neck (8th ed., 2017)

Primary Tumor (T) Distant Metastasis (M) T3 Tumors limited to the mucosa and immediately underlying soft M0 No distant metastasis tissue, regardless of thickness or greatest dimension; for example, M1 Distant metastasis polypoid nasal disease, pigmented or nonpigmented lesions of the oral cavity, pharynx, or larynx Histologic Grade (G) T4 Moderately advanced or very advanced disease No recommended histologic grading system at this time. T4a Moderately advanced disease Tumor involving deep soft tissue, cartilage, bone, or overlying skin Prognostic Stage Groups T4b Very advanced disease Tumor involving brain, dura, skull base, lower cranial nerves No prognostic stage grouping is proposed at this time. (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, or mediastinal structures

Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Regional lymph node metastases present

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-17 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

This discussion is being updated to correspond with the Principles of Nutrition and Supportive Care ...... MS-14 Discussion newly updated algorithm. Last updated 05/18/17 Principles of Dental Evaluation and Management ...... MS-15 NCCN Categories of Evidence and Consensus Cancer of the Lip ...... MS-16 Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Cancer of the Oral Cavity ...... MS-17

Category 2A: Based upon lower-level evidence, there is uniform Cancer of the Oropharynx ...... MS-19 NCCN consensus that the intervention is appropriate. Cancer of the Hypopharynx ...... MS-24 Category 2B: Based upon lower-level evidence, there is NCCN Cancer of the Nasopharynx ...... MS-26 consensus that the intervention is appropriate. Cancer of the Larynx ...... MS-28 Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. Paranasal Tumors (Maxillary and Ethmoid Sinus Tumors) ...... MS-31

All recommendations are category 2A unless otherwise noted. Very Advanced Head and Neck Cancers ...... MS-32

Occult Primary Cancer ...... MS-37

Table of Contents Salivary Gland Tumors ...... MS-39

Overview ...... MS-2 Mucosal Melanoma of the Head and Neck ...... MS-40

Literature Search Criteria and Guidelines Update Methodology .... MS-2 Recommended Reading List ...... MS-42

Incidence and Etiology ...... MS-2 Figure 1: Anatomic Sites and Subsites of the Head and Neck .... MS-44

Staging ...... MS-3 Figure 2: Level Designation for Cervical Lymphatics in the Right Neck ...... MS-44 Management Approaches ...... MS-4 References ...... MS-45 Comorbidity and Quality of Life ...... MS-5

Head and Neck Surgery...... MS-6

Head and Neck Radiation Therapy ...... MS-9

Version 1.2018, 02/15/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-1 Printed by Anton Kabakov on 3/5/2018 6:52:58 AM. For personal use only. Not approved for distribution. Copyright © 2018 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Overview The search results were narrowed by selecting studies in humans The NCCN Guidelines for Head and Neck Cancers address tumors published in English. Results were confined to the following article arising in the lip, oral cavity, pharynx, larynx, and paranasal sinuses types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, (see Figure 1); occult primary cancer, salivary gland cancer, and Phase IV; Practice Guideline; Guidelines; Randomized Controlled Trial; mucosal melanoma (MM) are also addressed.1,2 Much recent progress Meta-Analysis; Systematic Reviews; and Validation Studies. has been made during the last 10 years in understanding the The PubMed search resulted in 114 citations, and their potential epidemiology, pathogenesis, and management of head and neck (H&N) relevance was examined. The data from key PubMed articles and cancers.3 articles from additional sources deemed as relevant to these guidelines By definition, the NCCN Guidelines cannot incorporate all possible and discussed by the panel have been included in this version of the clinical variations and are not intended to replace good clinical judgment Discussion section (eg, e-publications ahead of print, meeting or individualization of treatments. Exceptions to the rule were discussed abstracts). Recommendations for which high-level evidence is lacking among the panel members while developing these NCCN Guidelines. A are based on the panel’s review of lower-level evidence and expert 5% rule (omitting clinical scenarios that comprise less than 5% of all opinion. cases) was used to eliminate uncommon clinical occurrences or The complete details of the Development and Update of the NCCN conditions from these NCCN Guidelines. Guidelines are available on the NCCN website (www.NCCN.org). Literature Search Criteria and Guidelines Update Methodology Incidence and Etiology In 2017, it is estimated that about 63,030 new cases of oral cavity, Prior to the update of this version of the NCCN Guidelines for Head and pharyngeal, and laryngeal cancers will occur, which account for about Neck Cancers, an electronic search of the PubMed database was 3.7% of new cancer cases in the United States.5 An estimated 13,360 performed to obtain key literature in the field of H&N cancers published deaths from H&N cancers will occur during the same time period.5 between July 18, 2015 and June 25, 2016, using the following search Squamous cell carcinoma or a variant is the histologic type in more than terms: (head and neck cancer) OR (lip cancer) OR (oral cavity cancer) 90% of these tumors. Alcohol and tobacco abuse are common etiologic OR (oropharynx cancer) OR (hypopharynx cancer) OR (nasopharynx factors in cancers of the oral cavity, oropharynx, hypopharynx, and cancer) OR (larynx cancer) OR (paranasal tumor) OR (ethmoid sinus larynx. Because the entire aerodigestive tract epithelium may be tumor) OR (maxillary sinus tumor) OR (salivary gland tumor) OR exposed to these carcinogens, patients with H&N cancers are at risk for (mucosal melanoma head) OR (mucosal melanoma neck). The PubMed developing second primary neoplasms of the H&N, lung, esophagus, database was chosen because it remains the most widely used and other sites that share these risk factors. resource for medical literature and indexes only peer-reviewed biomedical literature.4

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Human Papillomavirus Infection clinical trial showed no difference in the presence of distant metastasis Human papillomavirus (HPV) infection is now well accepted as a cause in patients with p16-positive disease, relative to patients with p16- 19 of squamous cancers of the oropharynx (particularly cancers of the negative disease. Additional analyses have suggested that tonsils and tongue base).6-13 The overall incidence of HPV-positive H&N individuals with matted nodes or N2c disease may have worse cancers is increasing in the United States, while the incidence of prognosis, and therefore should be excluded from deintensification 28-30 HPV-negative (primarily tobacco- and alcohol-related) cancer is trials. decreasing.14 Patients with HPV-associated H&N cancer tend to be younger.13,15 Oral HPV type 16 infection increases risk of oropharyngeal Staging cancer,6,12,16,17 and a strong causal relationship has been established.6,16 Stage at diagnosis predicts survival rates and guides management in th HPV types 18, 31, and 33 are responsible for the vast majority of the patients with H&N cancers. The 2010 AJCC staging classification (7 remaining fraction.13 Expression of HPV E6 and E7 oncogenes edition) was used as a basis for NCCN's treatment recommendations 31,32 inactivates the tumor-suppressor proteins p53 and pRb, respectively, for H&N cancers. The TNM staging systems developed by the AJCC which leads to development of cancer.18 No formal prospective studies for the lip and oral cavity, pharynx (nasopharynx, oropharynx, and of the efficacy of HPV vaccines in the prevention of oral HPV infections hypopharynx), larynx (glottis and supraglottis), paranasal sinuses have been conducted, and therefore further studies are warranted. (ethmoid and maxillary), major salivary glands (parotid, submandibular, and sublingual), and MM are shown in Tables 1 to 6, respectively.32 Analyses from clinical trials indicate that patients with locally advanced Definitions for regional lymph node (N) involvement and spread to HPV-positive H&N cancers have improved response to treatment and distant metastatic sites (M) are uniform except for N staging of survival (overall and progression-free) when compared with nasopharyngeal carcinoma (see Table 2). Definitions for staging the HPV-negative tumors,19-23 with one analysis showing that p16-positive primary tumor (T), based on its size, are uniform for the lip, oral cavity, non-oropharyngeal squamous H&N cancers have better prognosis, and oropharynx. In contrast, T stage is based on subsite involvement relative to p16-negative non-oropharyngeal cancers.24 Treatment and is specific to each subsite for the glottic larynx, supraglottic larynx, response is improved in patients receiving both chemoradiation19,20 and hypopharynx, and nasopharynx. In general, stage I or II disease defines conventional radiation therapy.25 a relatively small primary tumor with no nodal involvement. Stage III or IV cancers include larger primary tumors, which may invade underlying The relationship between HPV and other prognostic or predictive structures and/or spread to regional nodes. Distant metastases are 26,27 factors such as smoking history and stage has been investigated. uncommon at presentation. More advanced TNM stages are associated For example, analyses of patients with oropharyngeal cancer who with worse survival. Protocols for the specific sites from the College of were enrolled in RTOG 9003 or 0129 (n = 165) showed that smoking American Pathologists may also be useful. was associated with decreased overall and progression-free survival (PFS), regardless of p16 status.26 A retrospective analysis from a

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

In the 7th edition of the AJCC staging manual, the words resectable present with early-stage disease (stage I or II). The two most commonly (T4a) and unresectable (T4b) were replaced by the terms moderately employed modalities, surgery and RT, result in similar survival in these advanced (T4a) and very advanced (T4b).31 These changes were individuals. The choice of surgery or RT is often based on local deemed necessary, because a substantial proportion of institutional expertise and/or perceived relative morbidity of these advanced-stage malignancies of the H&N, although resectable, are treatment options. With evolving techniques of systemic therapy/RT and being treated non-surgically. Furthermore, a clear consensus in criteria less invasive surgery, morbidity too is a moving target. Combined for resectability can be difficult to obtain. For example, some tumors modality therapy is generally recommended for the approximately 60% deemed unresectable are in fact anatomically resectable, but surgery is of patients with locally or regionally advanced disease at diagnosis. not pursued because of medical contraindications to surgery or because it is anticipated that surgery will not improve prognosis (see Resectable The treatment of patients with locally advanced T4b or unresectable versus Unresectable Disease in this Discussion). This change in nodal disease, metastatic disease, or recurrent disease for the following terminology allows revising of stage IV disease into moderately sites (ie, lip, oral cavity, pharynx, larynx, paranasal sinus) and for occult advanced local/regional disease (stage IVA), very advanced primary cancer is addressed in the algorithm (see the NCCN Guidelines local/regional disease (stage IVB), and distant metastatic disease for Very Advanced Head and Neck Cancers). Participation in clinical (stage IVC) for many sites (ie, lip, oral cavity, oropharynx, hypopharynx, trials is a preferred or recommended treatment option in many larynx, paranasal sinuses, major salivary glands, MM). Of note, a situations. In formulating these NCCN Guidelines, panel members have designation of stage IV disease does not necessarily mean the disease tried to make them evidence-based while providing a statement of is incurable, particularly in the absence of distant metastases. MMs are consensus as to the acceptable range of treatment options. Patients rare, very aggressive tumors that mainly affect the nasal cavity and treated at high-volume centers tend to have better outcomes relative to 33,34 paranasal sinuses. Thus, melanomas confined to the mucosa only are patients treated at low-volume centers. T3; those with moderately advanced lesions (involving underlying Multidisciplinary Team Involvement cartilage or bone) are T4a, and very advanced primary tumors are T4b (see Table 6). The initial evaluation and development of a plan for treating the patient with H&N cancer requires a multidisciplinary team of health care Management Approaches providers with expertise in caring for these patients.35,36 Similarly, Treatment is complex for patients with H&N cancers. The specific site of managing and preventing sequelae after radical surgery, RT, and disease, stage, and pathologic findings guide treatment (eg, the systemic therapy (eg, pain, xerostomia, speech and swallowing appropriate surgical procedure, radiation targets, dose and problems, depression) requires professionals familiar with the 37,38 fractionation, indications for systemic therapy). Single-modality disease. Follow-up for these sequelae should include a treatment with surgery or radiation therapy (RT) is generally comprehensive H&N examination and supportive care and 35 recommended for the approximately 30% to 40% of patients who rehabilitation. Adequate nutritional support can help to prevent severe

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

weight loss in patients receiving treatment for H&N cancers; therefore, treatment selection. Comorbidity is known to be a strong independent patients should be encouraged to see a registered dietitian (see predictor for mortality in patients with H&N cancers,49-56 and comorbidity Principles of Nutrition: Management and Supportive Care in the NCCN also influences costs of care, utilization, and quality of life.57-59 Guidelines for Head and Neck Cancers and this Discussion).39 Dental Traditional indices of comorbidity include the Charlson index48 and the care for RT effects should be provided (see this Discussion and the Kaplan-Feinstein index and its modifications.49,60 The Adult Comorbidity Principles of Dental Evaluation and Management in the NCCN Evaluation-27 (ACE-27) is specifically for H&N cancers and has Guidelines for Head and Neck Cancers). Tobacco use is associated excellent emerging reliability and validity.61,62 with at least 30% of cancer deaths.40 Therefore, patients’ tobacco use history should be assessed. Patients should be encouraged to stop Quality of Life smoking (and remain abstinent) and to modify alcohol consumption if Health-related quality-of-life issues are paramount in H&N cancers. excessive, because these habits may decrease the efficacy of treatment These tumors affect basic physiologic functions (ie, the ability to chew, and adversely affect other health outcomes.41,42 Programs using swallow, and breathe), the senses (ie, taste, smell, hearing), and behavioral counseling combined with medications that promote smoking uniquely human characteristics (ie, appearance, voice). Health status cessation (approved by the FDA) can be very useful describes an individual’s physical, emotional, and social capabilities and (www.smokefree.gov/). Follow-up care may include chest CT (with or limitations. Function and performance refer to how well an individual is without contrast) for patients with a smoking history (see NCCN able to perform important roles, tasks, or activities. Quality of life differs, Guidelines for Lung Cancer Screening, available at www.NCCN.org). because the central focus is on the value (determined by the patient Patients are at risk for depression from H&N cancer and its sequela, so alone) that individuals place on their health status and function.63 screening for depression is advised (see the NCCN Guidelines for 64 Distress Management, available at www.NCCN.org).43-46 Specific An NIH-sponsored conference recommended the use of components of patient support and follow-up are listed in the algorithm patient-completed scales to measure quality of life. For H&N (see Team Approach in the NCCN Guidelines for Head and Neck cancer-specific issues, the 3 validated and accepted measures are: 1) 65 Cancers). Panel members also recommend referring to the NCCN the University of Washington Quality of Life scale (UW-QOL); 2) the Guidelines for Palliative Care, Adult Cancer Pain, and Smoking European Organization for Research and Treatment of Cancer Quality 66 Cessation as needed (available at www.NCCN.org). of Life Questionnaire (EORTC-HN35); and 3) the Functional Assessment of Cancer Therapy Head and Neck module (FACT-H&N).67 Comorbidity and Quality of Life The Performance Status Scale is a clinician-rated performance scale that is widely used for patients with H&N cancers.68 Comorbidity Comorbidity refers to the presence of concomitant disease (in addition to H&N cancers) that may affect diagnosis, treatment, and prognosis.47- 49 Documentation of comorbidity is important to facilitate optimal

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Head and Neck Surgery densely involve the cervical vertebrae, brachial plexus, deep muscles of Principles of Surgery the neck, or carotid artery (see Principles of Surgery in the NCCN Guidelines for Head and Neck Cancers). Tumor involvement of certain All patients should be evaluated by an H&N surgical oncologist before sites is associated with poor prognosis (ie, direct extension of neck treatment. In addition, it is critical that multidisciplinary evaluation and disease to involve the external skin; direct extension to mediastinal treatment be well coordinated. Evaluation, integration of therapy, structures, prevertebral fascia, or cervical vertebrae). assessment of resectability, primary tumor resection, margins, surgical management of cranial nerves (VII, X–XII), neck management, Unresectable tumors (ie, those tumors that cannot be removed without management of recurrences, and surveillance (including post-treatment causing unacceptable morbidity) should be distinguished from neck evaluation) are discussed in the algorithm (see Principles of inoperable tumors in those patients whose constitutional state precludes 69,70 Surgery in the NCCN Guidelines for Head and Neck Cancers). an operation (even if the cancer could be readily resected with few Resectable disease, neck dissection, postoperative management, and sequelae). Additionally, a subgroup of patients will refuse surgical surgical options for relapsed or refractory disease are discussed in the management, but their tumors should not be deemed unresectable. following sections. Minimally invasive surgery may be useful for Although local and regional disease may be surgically treatable, 71,72 decreasing morbidity. Use of robotic surgery is increasing in the patients with distant metastases are usually treated as though the United States. For H&N cancer surgery, transoral resection using primary tumor was unresectable. Thus, patient choice or a physician’s robotic, endoscopic, or direct access surgery may offer advantages over expectations regarding cure and morbidity will influence or determine 73,74 conventional methods. treatment. Patients with resectable tumors who can also be adequately treated without surgery represent a very important group. Definitive Resectable Versus Unresectable Disease treatment with RT alone or RT combined with systemic therapy may The term unresectable has resisted formal definition by H&N cancer represent equivalent or preferable approaches to surgery in these specialists. The experience of the surgeon and the support available individuals. Although such patients may not undergo surgery, their from reconstructive surgeons, physiatrists, and prosthodontists often tumors should not be labeled as unresectable. Their disease is usually strongly influence recommendations, especially in institutions where far less extensive than those with disease that truly cannot be removed. only a few patients with locally advanced H&N cancers are treated. The NCCN Member Institutions have teams experienced in the treatment of Neck Dissection H&N cancers and maintain the multidisciplinary infrastructure needed Historically, cervical lymph node (ie, neck) dissections have been for reconstruction and rehabilitation. A patient’s cancer is deemed classified as radical or modified radical procedures. The less radical unresectable if H&N surgeons at NCCN Member Institutions do not procedures preserved the sternocleidomastoid muscle, jugular vein, think they can remove all gross tumor on anatomic grounds or if certain spinal accessory nerve, or selective lymph node levels. The NCCN local control will not be achieved after surgery (even with the addition of Panel prefers to classify cervical lymphadenectomy using contemporary RT to the treatment approach). Typically, these unresectable tumors

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

nomenclature; thus, cervical lymph node dissections are classified as metastasis beyond the confines of an appropriate selective neck either comprehensive or selective.75 A comprehensive neck dissection dissection (<10% of the time).80-82 is one that removes all lymph node groups that would be included in a classic radical neck dissection. Whether the sternocleidomastoid The chief role of selective neck dissections in these NCCN Guidelines is muscle, jugular vein, or spinal accessory nerve is preserved does not to determine which patients are candidates for possible adjuvant affect whether the dissection is classified as comprehensive. Depending therapy (ie, systemic therapy/RT or RT), although selective neck 83 on the site, comprehensive neck dissection is often recommended for dissections may be used as treatment when neck tumor burden is low. N3 disease (see the algorithm for specific sites and Neck Management In general, patients undergoing selective neck dissection should not in Principles of Surgery in the NCCN Guidelines for Head and Neck have clinical nodal disease; however, selective neck dissection may Cancers). An analysis of clinical trial data (N = 572) showed that higher prevent morbidity in patients with nodal disease and may be appropriate 84-86 lymph node count (specifically 18 or more) from neck dissection was in certain patients with N1 to N2 disease. In the NCCN Guidelines, associated with greater overall survival (HR, 1.38; 95% CI, 1.09–1.74; P patients with cervical node metastases who undergo operations with = .007) and less locoregional failure (HR, 1.46; 95% CI, 1.02–2.08; P = therapeutic intent are generally treated with comprehensive neck .04).76 dissections, because often they have disease outside the bounds of selective neck dissections. Determining whether an ipsilateral or Selective neck dissections have been developed based on the common bilateral neck dissection is needed depends on tumor thickness, the pathways for spread of H&N cancers to regional nodes (see Figure extent of the tumor, and the site of the tumor.69 For example, bilateral 2).77,78 Depending on the site, selective neck dissection is often neck dissection is often recommended for tumors at or near the midline recommended for N0 disease (see the algorithm for specific sites and and/or for tumor sites with bilateral drainage. Neck Management in Principles of Surgery in the NCCN Guidelines for Head and Neck Cancers). To remove the nodes most commonly Careful and regular follow-up examinations by a trained H&N surgical involved with metastases from the oral cavity, a selective neck oncologist are recommended for nonsurgically treated patients so that dissection is recommended that includes the nodes found above the any local or regional recurrence is detected early, and surgery for omohyoid muscle (levels I–III and sometimes the superior parts of level relapsed/refractory disease (and neck dissection as indicated) is V).75,79 Similarly, to remove the nodes most commonly involved with performed. After either RT or chemoradiation, post-treatment evaluation metastases from the pharynx and larynx, a selective neck dissection is with imaging (ie, CT and/or MRI with contrast, FDG–PET/CT) guides recommended that includes the nodes in levels II to IV and level VI the use of neck dissection (see Post Chemoradiation or RT Neck 87-90 when appropriate.75 Elective level VI dissections are often considered Evaluation in the NCCN Guidelines for Head and Neck Cancers). If appropriate for infraglottic laryngeal cancers. H&N squamous cell PET/CT is used for follow-up, the first scan should be performed at a cancer with no clinical nodal involvement rarely presents with nodal minimum of 12 weeks after treatment to reduce the false-positive rate.88,91 A meta-analysis including 23 studies of FDG-PET/CT showed good diagnostic performance, with sensitivity and specificity values for

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

detection of recurrence of H&N cancer being 0.92 (95% CI, 0.90–0.94) The US Intergroup trial (RTOG 9501) randomly assigned patients with 2 and 0.87 (95% CI, 0.82–0.90), respectively.92 or more involved nodes, positive margins, or extracapsular nodal spread of tumor to receive standard postoperative RT or the same RT Note that a complete clinical response (ie, clinically negative) may be plus cisplatin (100 mg/m2 every 3 weeks for 3 doses).101 Note that defined as no visible or palpable neck disease and no radiographic long-term results from RTOG 9501 have been published.102 The findings (ie, the absence of either focally abnormal lymph nodes or large European trial (EORTC 22931) was designed using the same 87,93 nodes [>1.5 cm]); a complete pathologic response requires chemotherapy treatment and similar RT dosing but also included as pathologic confirmation. If a complete clinical response has been high-risk factors the presence of perineural or perivascular disease and achieved in patients who were N0 at initial staging, all of the panel nodal involvement at levels 4 and 5 from an oral cavity or oropharyngeal 87,93,94 members recommend observing the patient. In patients who have cancer.100 The RTOG trial showed statistically significant improvement a clinically negative neck, a negative PET/CT is 90% reliable and further in locoregional control and disease-free survival (DFS) but not overall 95-97 imaging is optional. Panel members also concur that any patient with survival, whereas the EORTC trial found significant improvement in residual disease or suspected progression in the neck after RT or survival and the other outcome parameters. A schedule using cisplatin 87 chemoradiation should undergo a neck dissection. For patients with at 50 mg intravenously weekly has also been shown to improve survival more equivocal PET/CT scan results in the neck, a prospective study in this setting in a randomized trial.104 suggests that a repeat PET/CT scan 4 to 6 weeks later may help identify those patients who can be safely observed without surgery to To better define risk, a combined analysis of prognostic factors and the neck.98 PET/CT surveillance in patients with advanced nodal outcome from the 2 trials was performed. This analysis showed that disease who received systemic therapy/RT yields a comparable survival patients in both trials with extracapsular nodal spread of tumor and/or rate and quality of life and may be more cost effective, relative to positive resection margins benefited from the addition of cisplatin to planned neck dissection.99 postoperative RT. For those with multiple involved regional nodes without extracapsular spread, there was no survival advantage.102,103 Postoperative Management of High-Risk Disease The NCCN panel noted that the combined analysis was considered Many factors influence survival and locoregional tumor control in exploratory by the authors, because it was not part of the initial protocol patients with H&N cancers. The role of systemic therapy/RT in the design.103 These publications form the basis for the NCCN postoperative management of the patient with adverse prognostic risk recommendations. factors has been clarified by 2 separate multicenter randomized trials for patients with high-risk cancers of the oral cavity, oropharynx, larynx, In NCCN Member Institutions, patients with extracapsular nodal spread or hypopharynx;100,101 long-term follow-up has been reported for one of and/or positive surgical margins receive adjuvant chemoradiotherapy 104-110 the trials.102 A combined analysis of data from the 2 trials has been after surgery. The presence of other adverse risk factors—multiple done.103 positive nodes (without extracapsular nodal spread), vascular/lymphatic/perineural invasion, pT3 or pT4 primary, and oral

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

cavity or oropharyngeal primary cancers with positive level 4 or 5 tissue changes, and this may result in a delayed diagnosis of persistent nodes—are established indications for postoperative RT. Because or recurrent disease. patients with these other adverse features were also included in the EORTC 22931 trial that showed a survival advantage for patients Panel members also emphasized the increased risk of complications receiving cisplatin concurrent with postoperative RT compared to RT when surgery in patients with relapsed/refractory disease is attempted. alone, the NCCN panel added consider chemoradiation for these Some of these patients may require microvascular free flap features.100 reconstruction to cover the defects at the primary site. The patients undergoing neck dissection may develop complications related to In the randomized phase II RTOG-0234 trial, two regimens in patients delayed wound healing, skin necrosis, or carotid exposure. with stage III and IV squamous cell carcinoma of the H&N were Laryngectomy may be indicated to obtain clear surgical margins or to compared: 1) adjuvant chemoradiotherapy with cetuximab and prevent aspiration (eg, in patients with advanced oropharyngeal docetaxel, and; 2) adjuvant chemoradiotherapy with cetuximab and cancer). After laryngectomy for relapsed/refractory disease, patients weekly cisplatin (N = 238).111 After a median follow-up of 4.4 years, may have a higher incidence of pharyngocutaneous fistula and flaps patients randomized to receive docetaxel experienced a 31% reduction may be advantageous (either a free flap reconstruction of the in DFS failure rate (HR, 0.69; 95% CI, 0.50—0.96; P = 0.01), and a 44% laryngopharyngeal defect, or a myocutaneous flap to buttress the suture reduction in mortality (HR, 0.56; 95% CI, 0.39—0.82; P = 0.001). line if the pharynx can be closed primarily). Chemoradiotherapy with cetuximab and docetaxel is continuing to be investigated in a randomized controlled trial (RCT) and is currently not Head and Neck Radiation Therapy recommended by the NCCN panel as an adjuvant systemic therapy/RT RT for H&N cancers has grown increasingly complex. The availability regimen. and technical precision of techniques such as intensity-modulated RT (IMRT) has markedly increased, perhaps beyond our ability to estimate Surgery for Relapsed/Refractory Disease the location of small subsites of microscopic disease. A thorough Patients with advanced carcinoma (any T, N2–3) who undergo understanding of natural history, anatomy, clinical circumstances, and nonsurgical treatment, such as concurrent chemotherapy and RT, need imaging continue to guide the use of radiation as primary or adjuvant very close follow-up both to evaluate for local recurrence and to assess treatment. The NCCN Guidelines for Radiation Therapy are not for ipsilateral or contralateral neck recurrence (see Follow-up all-inclusive. Although technical guidelines are rapidly evolving and Recommendations in the NCCN Guidelines for Head and Neck becoming more specific, advanced technologies provide much Cancers). For patients who do not have a complete clinical response to opportunity for variations and individualization in targeting and dose systemic therapy/RT, surgery plus neck dissection is recommended as delivery, challenging traditional notions of standard fields and targets. indicated. However, all panel members emphasized that it may be Guidelines from the American College of Radiology may be useful for difficult to detect local or regional recurrence due to radiation-related technical details (http://www.acr.org/Quality-Safety). The maximum

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

dose limits are 70 Gy (2 Gy/fraction) for the following sites: lip, oral on clinical circumstances. External-beam radiation doses exceeding 72 cavity, oropharynx, hypopharynx, glottic larynx, supraglottic larynx, Gy using conventional fractionation (2.0 Gy/fraction) may lead to occult primary, salivary gland tumors, and MM. For patients with cancer unacceptable rates of normal tissue injury.117,120-124 When using of the pharynx and who have high-risk subclinical disease, a hyperfractionation, high-risk sites generally require up to 81.6 Gy (1.2 fractionation schedule of 69.96 Gy at 2.12 Gy/fraction daily (Monday– Gy/fraction).117,118 Friday) for 6 to 7 weeks is recommended.112 In contrast, elective irradiation to low-risk and intermediate-risk sites Although several palliative RT regimens are provided, no single regimen requires 44 Gy (2.0 Gy/fraction) to 63 Gy (1.6–1.8 Gy/fraction), is preferred; specific regimens vary widely among NCCN Member depending on the estimated level of tumor burden, and on whether 3-D Institutions.113-115 Any palliative RT regimen that might cause severe conformal RT or IMRT is used. For 3-D conformal RT and sequentially toxicities should be avoided. More hypofractionated regimens may be planned IMRT, suggest 44 to 50 Gy (2.0 Gy/fraction).125,126 For IMRT, useful for patients with end-stage disease. For example, the QUAD suggest 54 to 63 Gy (1.6–1.8 Gy/fraction).126-128 Postoperative irradiation SHOT regimen consists of a dose of 44.4 Gy, delivered in 12 fractions is recommended based on stage, histology, and surgical-pathologic over 3 cycles.116 findings. In general, postoperative RT is recommended for selected risk factors, including advanced T-stage, depth of invasion, multiple positive Radiation Doses nodes (without extracapsular nodal spread), or Selection of radiation total dose depends on the primary tumor and neck perineural/lymphatic/vascular invasion. Higher doses of postoperative node size, fractionation, and clinical circumstances, including whether to RT alone (60–66 Gy), or with systemic therapy, are recommended for use concurrent systemic therapy (see Radiation Techniques in the the high-risk features of extracapsular disease and/or positive NCCN Guidelines for Head and Neck Cancers and see the individual margins.102,103 The preferred interval is 6 weeks or less, between Principles of Radiation Therapy for each primary site). The resection and commencement of postoperative RT. demonstration of significant dose sparing of organs at risk (eg, brain, cochlea, optic chiasm and nerves, spinal cord) reflects best clinical Fractionation in RT Alone practice. Target definition and delineation is crucial, and imaging should No single fractionation schedule has proven to be best for all tumors. be used to ensure accurate radiation delivery. Data strongly indicate that squamous cancers of the H&N can grow rapidly and may compensate for RT-induced cell loss through the When using conventional definitive fractionation, the primary tumor and mechanism of accelerated repopulation.129-131 Especially in RT alone involved lymph nodes (ie, high-risk sites) generally require a total of 66 settings, schedules delivering at least 1000 cGy per week are 117-119 Gy (2.2 Gy/fraction) to 70 Gy (2.0 Gy/fraction). For doses greater recommended,132-136 with the exception of salivary gland tumors, which than 70 Gy, some clinicians feel that the fractionation should be slightly may have slower cell kinetics. Trials in early-stage glottic laryngeal modified (eg, <2.0 Gy/fraction for at least some of the treatment) to minimize toxicity; an additional 2 to 3 doses can be added depending

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

cancer have shown higher recurrence rates with daily fraction sizes worse late effects reported at 6 to 24 months after treatment start, <200 cGy where the cumulative weekly dose is <1000 cGy.137,138 among the various treatment groups. Long-term follow-up confirmed a statistically significant improvement in locoregional control and overall Two large, randomized trials from Europe have reported improved survival with hyperfractionation compared to standard fractionation.118 locoregional control using altered fractionation. The EORTC protocol 22791 compared hyperfractionation (1.15 Gy twice daily, or 80.5 Gy A meta-analysis of updated individual patient data from 15 randomized over 7 weeks) with conventional fractionation (2 Gy once daily, or 70 Gy trials analyzed the effect of hyperfractionated or accelerated RT on over 7 weeks) in the treatment of T2, T3, N0-1 oropharyngeal survival of patients with H&N cancers.143 Standard fractionation carcinoma excluding base of tongue primaries. At 5 years, a statistically constituted the control arm in all of the trials in this meta-analysis.119 An significant increase in local control was observed in the absolute survival benefit for altered fractionation of 3.4% at 5 years (HR hyperfractionation arm (38% vs. 56%; P = .01) and no increase in late 0.92; 95% CI, 0.86–0.97; P = .003) was reported. This benefit, however, complications was observed.139 A long-term follow-up analysis has also was limited to patients younger than 60 years of age.143 shown a small survival advantage for hyperfractionation (P = .05).140 Hyperfractionation was associated with a benefit of 8% after 5 years.144 Another EORTC protocol (22851) compared accelerated fractionation However, the GORTEC 99-02 trial reported that altered fractionation did (1.6 Gy 3 times daily, or 72 Gy over 5 weeks) with conventional not improve outcomes when compared with conventional fractionation (1.8–2.0 Gy once daily, or 70 Gy over 7–8 weeks) in fractionation.145,146 Consensus regarding altered fractionation schedules various intermediate to advanced H&N cancers (excluding cancers of with concomitant boost or hyperfractionation for stage III or IV oral the hypopharynx). Patients in the accelerated fractionation arm had cavity, oropharynx, supraglottic larynx, and hypopharyngeal squamous significantly better locoregional control at 5 years (P = .02). cell cancers has not yet emerged among NCCN Member Disease-specific survival showed a trend in favor of the accelerated Institutions.143,147,148 fractionation arm (P = .06). Acute and late toxicity were increased with acceleration, however, raising questions about the net advantages of Fractionation in Concurrent Chemoradiation accelerated fractionation.141 Panel members do not agree about the optimal radiation dose fractionation scheme to use with concurrent systemic therapy. Most The RTOG reported the results of a 4-armed, phase III, randomized published studies have used conventional fractionation (at 2.0 clinical trial (RTOG 90-03) comparing hyperfractionation and 2 variants Gy/fraction to a typical dose of 70 Gy in 7 weeks) with single-agent 117,118,142 of accelerated fractionation versus standard fractionation. After 2 high-dose cisplatin (given every 3 weeks at 100 mg/m2).19 Other fraction years of follow-up, both accelerated fractionation with a concomitant sizes (eg, 1.8 Gy, conventional), other dosing schedules of cisplatin, boost (AFX-C) and hyperfractionation were associated with improved other single agents, multiagent systemic therapy, and altered locoregional control and DFS compared with standard fractionation. fractionation with systemic therapy have been evaluated alone or in However, acute toxicity was increased with accelerated fractionation. combination. Numerous trials have shown that modified fractionation No significant difference was shown in the frequency of grade 3 or

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

and concurrent chemotherapy are more efficacious than modified radiation planning, hot spots associated with higher toxicity can fractionation alone.148-152 RTOG 0129 assessed accelerated occur.179,180 Alternatively, separate dose plans for the low versus higher fractionation with 2 cycles of concurrent cisplatin versus standard dose targets can be delivered sequentially (reduce target size and fractionation with 3 cycles of concurrent cisplatin. There was no boost) or on the same day as separate fractions in twice-a-day schemas significant difference in overall survival between the 2 arms.19,153,154 (see Radiation Techniques in the NCCN Guidelines for Head and Neck Cancers).171,181 Concurrent chemoradiation increases acute toxicity compared to radiation alone, although an increase in late toxicity beyond that caused IMRT is now widely used in H&N cancers and is the predominant by RT alone is less clear.155-157 Altered fractionation and/or multiagent technique used at NCCN Member Institutions.182,183 It is useful in systemic therapy may further increase the toxicity burden.158 For any reducing long-term toxicity in oropharyngeal, paranasal sinus, and chemotherapeutic approach, close attention should be paid to published nasopharyngeal cancers by reducing the dose to one or more major reports for the specific chemotherapy agent, dose, and schedule of salivary glands, temporal lobes, mandible, auditory structures (including administration. Chemoradiation should be performed by an experienced cochlea), and optic structures.127,166,174,184-191 Overall survival is similar team and should include substantial supportive care. between patients treated with IMRT and those receiving conventional RT.161,185,192,193 In-field recurrences, low-grade mucositis in areas away Radiation Techniques from the cancer targets, and posterior neck hair loss can occur with IMRT IMRT.194-197 The application of IMRT to other sites (eg, oral cavity, The intensity of the radiation beam can be modulated to decrease larynx, hypopharynx, salivary glands) is evolving.198-205 doses to normal structures without compromising the doses to the cancer targets.159,160 Over the last 15 years, IMRT has displaced other Reports indicate that xerostomia has decreased due to the transition to 161,163 techniques in the treatment of most H&N malignancies.161-167 IMRT is an IMRT from older 2D and 3D radiotherapy techniques. Numerous advanced form of conformal RT permitting more precise cancer phase II studies show a decrease in late toxicity (xerostomia) without targeting while reducing dose to normal tissues.126,168-172 Xerostomia is a compromising tumor control for nasopharyngeal, sinonasal, and other common long-term side effect of RT, which can be reduced with use of sites. Three randomized trials have supported the clinical benefits of IMRT, drug therapy (eg, pilocarpine, cevimeline), salivary substitutes, IMRT in H&N cancers with regard to the reduction in xerostomia. Pow et and other novel approaches (eg, acupuncture).166,173-177 al evaluated treatment of early-stage nasopharyngeal carcinoma with conventional RT techniques versus with IMRT.174 The results showed a IMRT dose painting refers to the method of assigning different dose statistical improvement in salivary flow and in patient-reported levels to different structures within the same treatment fraction (eg, 2.0 quality-of-life parameters.174 In the study by Kam et al, patients with to gross tumor, 1.7 to microscopic tumor, <1.0 Gy to parotid gland) nasopharyngeal carcinoma were randomly assigned to either IMRT or resulting in different total doses to different targets (eg, 70 Gy, 56 Gy, conventional 2D RT.166 At one year after treatment, patients in the IMRT <26 Gy).178,179 Although dose painting has been used to simplify arm had significantly lower rates of clinician-rated severe xerostomia

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

than patients in the 2D RT arm (39.3% vs. 82.1%; P = .001). Salivary Brachytherapy flow rates were also higher with IMRT. The mean parotid dose was 32 Brachytherapy is now being used less often because of improved local Gy in the IMRT group and 62 Gy in the conventional group. Although a control obtained with concurrent chemoradiation. However, trend for improvement in patient-reported dry mouth was observed after brachytherapy still has a role for lip and oral cavity cancers (see IMRT, recovery was incomplete and there was no significant difference Principles of Radiation Therapy in the NCCN Guidelines for Cancer of in patient-reported outcomes between the 2 arms. The authors the Lip and Cancer of the Oral Cavity).215 concluded that other salivary glands may also be important and merit protection. Proton Beam Therapy At present, proton therapy is the predominant particle therapy under Data from a phase III randomized trial (PARSPORT) indicate that IMRT active clinical investigation in the United States.216-219 Proton therapy has decreases xerostomia when compared with conventional RT in patients been used to treat oropharyngeal cancers, sinonasal malignancies, with non-nasopharyngeal carcinoma.161 In this trial, patients with T1-T4, adenoid cystic carcinomas, and MMs.220-225 A systematic review and N0-N3, M0 disease were treated to a total dose of 60 or 65 Gy in 30 meta-analysis of non-comparative observation studies concluded that fractions either with conventional RT (ie, parallel opposed technique) or patients with malignant diseases of the nasal cavity and paranasal with IMRT; 80 patients with oropharyngeal and 14 patients with sinuses who received proton therapy appeared to have better outcomes hypopharyngeal tumors were included. Grade 2 or worse (LENT-SOMA than those receiving photon therapy.226 A review of proton therapy in scale) xerostomia 2 years after treatment was seen in 83% of patients patients with H&N cancers included 14 retrospective reviews and 4 receiving conventional RT versus 29% of patients in the IMRT group (P prospective nonrandomized studies.217 The 2- to 5-year local control < .0001). No differences were seen in the rates of locoregional control rates were as low as 17.5% for T4 or recurrent paranasal sinus cancers or survival. and as high as 95% in other types of tumors.

IMRT may be useful to preserve the optic pathway in patients with In institutional reports, outcomes for proton therapy have been sinonasal malignancies.184 Retrospective analyses including 2,993 reported.217,227-229 Recent reports show that proton beam therapy (PBT) patients who received RT for treatment of H&N cancer showed that for treatment of sinonasal cancer is associated with good locoregional patients who received IMRT had a shorter duration of feeding tube control, freedom from distant metastasis, and acceptable toxicity.228,229 placement, compared to those who received 3D RT (P = .03).206 Another recent institutional report (N = 41) showed that PBT may be However, IMRT can create new unexpected acute toxicities to organs associated with greater normal tissue sparing without sacrificing target radiated in the beam path.207,208 In addition, the long-term effects, even coverage, which may be associated with reduced toxicity compared to with using IMRT, can still result in a substantial decrease in quality of IMRT.227 life.209-214 Results from a retrospective study comparing 40 patients with cancer of the nasopharynx, nasal cavity, or paranasal sinuses who received either

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

PBT or IMRT to the H&N (with or without chemotherapy) showed that Stereotactic Body Radiation Therapy PBT was associated with lower mean doses to the oral cavity, Stereotactic body RT (SBRT) is an advanced technique of external esophagus, larynx, and parotid glands, regardless of nodal status and beam RT (EBRT) that delivers large ablative doses of radiation. compared to IMRT.230 PBT was also associated with less dependence Advantages of SBRT include shorter treatment time, promising local on opioid pain medication and gastrostomy tube placement, compared control rates, and acceptable toxicity.238 There is currently insufficient to IMRT. evidence to recommend SBRT for treatment of H&N cancers, but the NCCN panel acknowledges that it might be beneficial for palliation or for Occasional fatal outcomes have been reported with proton therapy, older adults.239,240 including 3 deaths secondary to brainstem injury.231-233 A report from Japan described long-term toxicities after proton therapy in 90 patients Follow-up After RT 234 with nasal cavity, paranasal sinus, or skull base malignancies. Late For patients whose cancer has been treated with RT, the recommended toxicities reached grade 3 in 17 patients (19%) and grade 4 in 6 patients follow-up (see Follow-up Recommendations in the NCCN Guidelines for (7%) (encephalomyelitis infection in 2 patients, optic nerve disorder in 4 Head and Neck Cancers) includes an assessment of thyroid function patients). This rate of grade 3 to 4 late toxicity with protons (19%) was (ie, the thyroid-stimulating hormone [TSH] level should be determined 235 similar to the rate reported for conventional RT with photons (16%). every 6–12 months). Increased TSH levels have been detected in 20% Other clinicians have reported low rates of serious toxicities when using to 25% of patients who received neck irradiation; patients are at 221,236 strict dose limits for proton therapy. increased risk of hypothyroidism.241-243

Proton therapy has typically been used to treat patients with the most Principles of Nutrition and Supportive Care challenging disease, for which other RT options were not felt to be safe The Principles of Nutrition section outlines nutritional management and or of any benefit.221,224,237 As described above, nonrandomized supportive care for patients with H&N cancers who are prone to weight institutional reports and a small number of systemic reviews have loss, which can often be severe, as a result of treatment-related toxicity, shown that PBT may be safe to use in some settings. In patients with disease, and health behaviors such as poor nutritional habits.37,244,245 tumors that are periocular in location and/or invade the orbit, skull base, Patients with H&N cancers are also at risk for dehydration. The and/or cavernous sinus, and tumors that extend intracranially or exhibit multidisciplinary expertise of a registered dietitian and a extensive perineural invasion, as well as in patients being treated with speech-language/swallowing therapist should be utilized throughout the curative intent and/or have long life expectancies, achieving highly continuum of care. conformal dose distributions is crucial. An accurate comparison of benefits to other RT options should ideally take place in the controlled Patients who have had significant weight loss (5% body weight loss setting of randomized clinical trials. An alternative approach may be to over 1 month, or 10% body weight loss over 6 months) clearly need develop prospectively maintained databases to raise the quality of nutritional evaluation and close monitoring of their weight to prevent institutional reports of clinical experiences.233

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

further weight loss.246,247 In addition, all patients should receive dysfunction, which are associated with increased dental caries.258-261 In nutritional evaluation before and after treatment to assess the need for addition, RT to the dental hard tissues is also associated with bone interventions (eg, enteral support via feeding tubes).248-250 Patients are demineralization and trismus of the masticatory muscles. Using IMRT also at risk for problems with speech. Treatment and/or the progression and limiting the RT dose to the teeth have been shown to decrease of their disease may cause deterioration in their ability to speak and/or xerostomia and damage to the teeth.258,259,262-269 Dental/oral evaluation swallow.251-253 Evaluation by a speech-language/swallowing therapist is and management can help decrease dental caries and associated valuable before and after treatment, because it can help mitigate problems such as dentoalveolar infection and potential problems.254-256 Patients are also at risk for dental problems osteoradionecrosis.260,262,269-282 (see Principles of Dental Evaluation and Management in this Discussion and the NCCN Guidelines for Head and Neck Cancers).37 The recommended dental/oral evaluations before, during, and after RT are described in detail in the algorithm and summarized here. A NCCN Panel Members agree that reactive feeding tube placement is dental/oral treatment plan needs to be implemented before RT and appropriate in selected patients with H&N cancers.245,249 There is no should include the following: 1) eliminating potential sources of consensus about whether prophylactic tube placement is appropriate, infection; 2) performing any dental extractions at least 2 weeks before although this is commonly done if high-risk patients will be receiving RT; 3) treating active dental caries and periodontal disease; 4) treating intense multimodality therapy that is anticipated to cause severe oral candidiasis; and 5) educating patients about preventive problems (eg, concurrent chemoradiation).245,247,257 The NCCN strategies.270 Some of the strategies to decrease oral and dental Guidelines provide recommendations for prophylactic tube placement, complications include: 1) decrease dry mouth (eg, by using salivary which should be strongly considered in high-risk patients (eg, those with substitutes and stimulation);283-287 2) decrease dental caries (eg, by severe pretreatment weight loss, ongoing dehydration or dysphagia, using topical fluoride);271,288-292 3) decrease dentoalveolar infection (eg, significant comorbidities, severe aspiration, anticipated swallowing with frequent evaluations to detect and treat disease promptly); 4) issues) (see Principles of Nutrition: Management and Supportive Care decrease osteoradionecrosis (eg, by extracting teeth before RT);274 5) in the NCCN Guidelines for Head and Neck Cancers). The NCCN decrease trismus of the masticatory muscles (eg, by using custom Guidelines do not recommend prophylactic tube placement in lower-risk mouth-opening devices to maintain range of motion);293-295 and 6) have patients (ie, those without significant pretreatment weight loss, patient undergo evaluations during and after treatment to help minimize significant aspiration, or severe dysphagia), although these patients complications.283,284,290,296,297 need to carefully monitor their weight. During and after treatment, the goals of dental/oral management Principles of Dental Evaluation and Management include: 1) managing xerostomia; 2) preventing trismus; and 3) 270 Patients with H&N cancers are at risk of oral and dental complications detecting and treating oral candidiasis. Additional goals after after RT because of treatment-induced xerostomia and salivary gland treatment include: 1) preventing and treating dental caries; 2)

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

preventing postradiation osteonecrosis; and 3) preventing oral Treatment 270 candidiasis. Treatment of the Primary The treatment of lip cancer is governed by the stage of the disease. The Cancer of the Lip choice of a local treatment modality is based on the expected functional The NCCN Guidelines for squamous cell carcinoma of the lip generally and cosmetic outcome. In early-stage cancers (T1–2, N0), surgery is follow accepted clinical practice patterns established over several preferred, and radiation is an option for local control (see the NCCN decades. No randomized clinical trials have been conducted that can be Guidelines for Cancer of the Lip).298-300 Some very small or superficial used to direct therapy. The incidence of lymph node metastases cancers are managed more expeditiously with a surgical resection (especially in early-stage lower lip cancer) is low, averaging less than without resultant functional deformity or an undesired cosmetic result. A 10%. The risk of lymph node metastases is related to the location, size, superficial cancer that occupies most of the lower lip, however, is best and grade of the primary tumor. Elective neck dissection or neck managed with RT.301 Occult cervical metastases are not common in irradiation can be avoided in patients with early-stage disease and a patients with early-stage lip cancer, but sentinel lymph node biopsy clinically negative neck. Treatment recommendations are based on (SLNB) has been shown to be feasible and effective in patients who clinical stage, medical status of the patient, anticipated functional and may be at high risk of metastases based on tumor size and depth.302-304 cosmetic results, and patient preference. Some advanced lip cancers can cause a great deal of tissue destruction Workup and Staging and secondary deformity; surgery is preferred in this clinical setting. The workup for patients with squamous cell carcinoma of the lip Surgery is also preferred for advanced cancers with extension into the consists of a complete H&N examination, biopsy, and other appropriate bone. Patients who are unfit for surgery or who have M1 disease at studies (see Workup in the NCCN Guidelines for Cancer of the Lip). initial presentation should be treated as for very advanced disease (see Dental evaluation (dental panoramic x-ray), CT, and/or MRI with the NCCN Guidelines for Very Advanced Head and Neck Cancers).301 contrast is done as clinically indicated to better assess soft tissue or nodal spread or if bone invasion is suspected. Management of the Neck The management of the neck is also governed by stage and the The AJCC TNM staging system reflects tumor size, extension, and location of the tumor. For example, the lymphatics of the upper lip are nodal disease (see Table 1).31 This system does predict the risk for local very extensive. Thus, tumors in this location are more apt to spread to recurrence. The location of the primary tumor also is predictive. Tumors deep superior jugular nodes. The position of the tumor along the lip also in the upper lip and commissural areas have a higher incidence of can be helpful in predicting the pattern of lymph node spread. A midline lymph node metastases at the time of diagnosis. Systemic location can place a patient at higher risk for contralateral disease. For dissemination is rare, occurring in approximately 10% to 15% of patients with advanced disease (T3, T4a) and an N0 neck, an ipsilateral patients, most often in those with uncontrolled locoregional disease. or bilateral neck dissection is an option (see the NCCN Guidelines for Cancer of the Lip). When a patient presents with palpable disease, all

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

appropriate nodal levels should be dissected. In patients who appear to Cancer of the Oral Cavity have a complete response after either RT or chemoradiation, The oral cavity includes the following subsites: buccal mucosa, upper post-treatment evaluation with imaging can be used to guide the use of and lower alveolar ridge, retromolar trigone, floor of the mouth, hard neck dissection (see Principles of Surgery in the algorithm). palate, and anterior two thirds of the tongue. The area has a rich lymphatic supply, and initial regional node dissemination is to nodal Radiation Therapy groups at levels I to III. RT, when used as definitive treatment, may consist of EBRT with (or without) brachytherapy, depending on the size of the tumor. Regional node involvement at presentation is evident in approximately Brachytherapy should only be performed at centers with expertise. The 30% of patients, but the risk varies according to subsite. For example, NCCN algorithm provides recommendations for low-dose rate and primaries of the alveolar ridge and hard palate infrequently involve the high-dose rate brachytherapy (see Principles of Radiation Therapy in neck, whereas occult neck metastasis is common (50%–60%) in 305,306 the NCCN Guidelines for Cancer of the Lip). The conventional patients with anterior tongue cancers. In general, many patients fractionation dose required also depends on tumor size, but doses of 66 undergo either ipsilateral or bilateral neck dissection, which is guided by to 72 Gy are adequate to control the disease (see Principles of tumor thickness. If definitive RT is chosen for treatment of T1–2, N0 Radiation Therapy in the NCCN Guidelines for Cancer of the Lip). disease, the fraction size to the intermediate- and low-risk sites ranges from 44 Gy (2.0 Gy/fraction) to 60 Gy (1.6 Gy fraction) (see Principles of In the adjuvant setting, simple T1-T2 lesions are generally treated the Radiation Therapy in the NCCN Guidelines for Cancer of the Oral same as a skin lesion (see NCCN Guidelines for Non-Melanoma Skin Cavity). For these sites of suspected subclinical spread, suggested Cancer; available at www.NCCN.org). Otherwise, doses of 60 to 66 Gy doses are 44–54 Gy if 3D conformal RT is used or 54–60 Gy if IMRT is are required, depending on the pathologic features. In both definitive used, depending on the dose/fraction (1.6–2.0 Gy/fraction). and adjuvant settings, the neck is treated with doses that address adverse features, such as positive margins or invasion (perineural, Workup and Staging vascular, and/or lymphatic).307 The fraction size to the intermediate- and Imaging studies to evaluate mandibular involvement and a careful low-risk sites ranges from 44 Gy (2.0 Gy/fraction) to 60 Gy (1.6 Gy dental evaluation [including jaw imaging with Panorex or CT (with or fraction.) For these sites of suspected subclinical spread, suggested without contrast), as clinically indicated] are particularly important for doses are 44–54 Gy if 3D conformal RT is used or 54–60 Gy if IMRT is staging (see Table 1) and planning therapy for oral cavity cancers in used, depending on the dose/fraction (1.6–2.0 Gy/fraction). addition to a complete H&N examination, biopsy, and other appropriate Follow-up/Surveillance studies (see Workup in the NCCN Guidelines for Cancer of the Oral Cavity). For patients who appear to have stage III to IV disease, FDG- Recommendations for surveillance are provided in the algorithm (see PET/CT may alter management by upstaging patients.308 Nutrition, Follow-up Recommendations in the NCCN Guidelines for Head and speech, and swallowing evaluations are recommended for selected Neck Cancers).

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

at-risk patients (see Principles of Nutrition in this Discussion and in the effects model), compared to patients undergoing observation only.310 A NCCN Guidelines for Head and Neck Cancers). prospective RCT (n = 496) showed that patients receiving elective neck dissection had greater rates of overall survival (80% vs. 67.5%, P = Treatment 0.01) and DFS (69.5% vs. 45.9%, P < 0.001), relative to patients Surgery and RT are the recommended treatment options for early-stage receiving neck dissection after nodal relapse.311 Patients who received and locally advanced resectable lesions in the oral cavity. The specific elective neck dissection were less likely to have experienced nodal treatment is dictated by the TN stage and, if N0 at diagnosis, by the risk recurrence (29.6%), relative to patients who did not (45.1%). Subgroup of nodal involvement (see the NCCN Guidelines for Cancer of the Oral analyses from this study showed that elective neck dissection may be Cavity). Multidisciplinary team involvement is particularly important for most beneficial in patients with tumor thickness > 3mm, though this this site, because critical physiologic functions may be affected such as interaction was not statistically significant (P = 0.12). mastication, deglutition, and articulation of speech. Most panel members prefer surgical therapy for resectable oral cavity tumors, even SLNB may be used to identify occult cervical metastases (see Sentinel for more advanced tumors. The functional outcome after primary Lymph Node Biopsy in the Principles of Surgery in the NCCN 312-318 surgical management is often quite good, given advances in Guidelines for Head and Neck Cancers). However, SLNB should reconstruction using microvascular techniques. Therefore, organ be done in centers with expertise in this technique; it is less accurate for 312,313 preservation using systemic therapy has received less attention for the floor of the mouth tumors. Some diagnostic agents for use in SLNB initial management of patients with oral cavity cancers. Definitive RT in patients with squamous cell carcinoma of the oral cavity have been 319,320 may be offered to selected patients who are medically inoperable or evaluated (eg, technetium Tc99m tilmanocept), but the data are refuse surgery. currently too limited for the panel to recommend a specific agent.

For patients with early-stage oral cavity cancers, the recommended Postsurgical adjuvant treatment options depend on whether adverse initial options are resection (preferred) of the primary or definitive RT. It features are present. For patients with resected oral cavity cancers who is debatable whether or not patients with early-stage node-negative oral have the adverse pathologic features of extracapsular nodal spread with cavity cancers should receive elective neck dissection. A watchful [or without] a positive mucosal margin, postoperative systemic waiting approach reduces the risks associated with surgery, with one therapy/RT (preferred, category 1) is the recommended treatment. For retrospective analysis showing that early detection through patients with positive margins, re-resection is the preferred option. RT is ultrasonography may reduce the risk of recurrences (N = 77).309 A meta- another option, and systemic therapy/RT may be considered. For analysis including four studies with 283 patients with N0 oral cancer patients with other risk features, options include RT or to consider showed that elective neck dissection reduces the risk of disease- systemic therapy/RT. specific mortality (RR, 0.57; 95% CI, 0.36—0.89; P = 0.014 for fixed- For patients with advanced-stage, resected oral cavity cancers who effects model; RR, 0.59; 95% CI, 0.37—0.96; P = 0.034 for random- have the adverse pathologic features of extracapsular nodal spread with

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

or without a positive mucosal margin, recommended postoperative HPV Testing adjuvant options include: systemic therapy/RT (preferred, category 1) or The attributable fraction for HPV in newly diagnosed oropharyngeal 100-104 RT. Adjuvant treatment options for positive margins are the same, cancer is estimated at 60% to 70% in the United States and parts of the but re-resection is an option if technically feasible, with consideration of European Union.14,322-325 The association of tumor HPV status with subsequent RT. For other risk features—such as pT3 or pT4 primary, patient prognosis has led to clinical utility (see HPV and Treatment of N2 or N3 nodal disease, nodal disease in levels IV or V, perineural Oropharyngeal Cancer, below). However, there are currently no invasion, or vascular tumor embolism, RT alone is recommended, or diagnostic tests with regulatory approval. A few HPV testing options are systemic therapy/RT may be considered (see the NCCN Guidelines for available for use in the clinical setting. Expression of p16 as detected by Cancer of the Oral Cavity). immunohistochemistry (IHC) is a widely available surrogate biomarker that has very good agreement with HPV status as determined by HPV Follow-up/Surveillance E6/E7 mRNA expression.326-328 Other tests include HPV detection by Recommendations for surveillance are provided in the algorithm (see polymerase chain reaction (PCR) and in situ hybridization (ISH).326,328 Follow-up Recommendations in the NCCN Guidelines for Head and Sensitivity of IHC staining for p16 and PCR-based assay is high, though Neck Cancers). specificity is highest for ISH.328 A validation study of HPV testing methods showed that sensitivity and specificity of p16 IHC was 96.8% Cancer of the Oropharynx and 83.8%, respectively, with sensitivity and specificity of HPV16 ISH The oropharynx includes the base of the tongue, tonsils, soft palate, being 88.0% and 94.7%.326 Agreement between p16 IHC and ISH was and posterior pharyngeal wall. The oropharynx is extremely rich in good. The reduced specificity for p16 IHC may have been due to the lymphatics. Depending on the subsite involved, 15% to 75% of patients presence of p16-positive tumors that do not have evidence of HPV present with lymph node involvement. DNA, while the reduced sensitivity for HPV16 ISH may have been due to the presence of other high-risk HPV types in the tumor. Due to Workup and Staging variations in sensitivity and specificity values of testing options, multiple A multidisciplinary consultation is encouraged including a registered methods may be used in combination for HPV detection.13,328-330 dietitian and a speech-language/swallowing therapist (see Principles of Sufficient pathologic material for HPV testing can be obtained by Nutrition in this Discussion and in the NCCN Guidelines for Head and fine-needle aspiration (FNA).13,331 HPV testing may prompt questions Neck Cancers). Accurate staging (see Table 2) depends on a complete about prognosis (ie, a favorable or a less favorable forecast) and sexual H&N examination and appropriate imaging studies (see Workup in history that the clinician should be prepared to address. NCCN Guidelines for Cancer of the Oropharynx).31,321 Tumor HPV testing is recommended for cancers of the oropharynx, because prior Treatment HPV infection is related to the development of a significant proportion of The treatment algorithm has been divided into 3 staging categories: 1) oropharyngeal cancers (see the next section on HPV Testing). T1-2, N0-1; 2) T3-4a, N0-1; and 3) any T, N2-3. Of note, the following

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

categories are treated as advanced cancer: 1) T4b, any N; 2) Concurrent systemic therapy/RT—with high-dose cisplatin as the unresectable nodal disease; 3) unfit for surgery; or 4) M1 disease at preferred systemic agent—is recommended for treatment of locally or initial presentation (see the NCCN Guidelines for Very Advanced Head regionally advanced (T3-4a, N0-1, or any T, N2-3) cancer of the and Neck Cancers). oropharynx (see Principles of Systemic Therapy in the NCCN Guidelines for Head and Neck Cancers). Many panel members did not Early-stage (T1-2, N0-1) oropharyngeal cancers may be treated with: 1) agree that induction chemotherapy should be recommended for locally primary surgery—more specifically, transoral or open resection of the or regionally advanced cancer of the oropharynx. This disagreement is 71,74,332,333 primary—(with or without neck dissection); or 2) definitive RT. reflected by the category 3 recommendations for oropharyngeal cancer Panel members felt that the third option of RT plus systemic therapy (see The Induction Chemotherapy Controversy in this Discussion and (category 2B for systemic therapy) was only appropriate for T2, N1 (see the NCCN Guidelines for Cancer of the Oropharynx).155,335-344 Note that a the NCCN Guidelines for Cancer of the Oropharynx). Note that a category 3 recommendation indicates that only a few panel members category 2B recommendation indicates that most, but not all, panel agree (<25%) that the intervention is appropriate; most disagree. Most members agree that the intervention is appropriate (>50% but <85%). panel members agree that concurrent systemic therapy with RT should be used to treat fit patients with locally advanced disease. For patients with positive margins, re-resection is the preferred option for adjuvant treatment. RT is another option, and systemic therapy/RT HPV and Treatment of Oropharyngeal Cancer may be considered. For patients with other risk features, options include HPV status is a predictor of oropharyngeal cancer prognosis. A RT or consideration of systemic therapy/RT. Adjuvant systemic systematic review including 56 prospective or retrospective studies therapy/RT is recommended for adverse pathologic features of showed that patients with p16-positive oropharyngeal cancer had a extracapsular nodal spread with (or without) positive mucosal better prognosis and fewer rates of adverse events, relative to patients 100,101,103 margins. with p16-negative disease.345 Further, patients with p16-negative disease had worse outcomes following radiation treatment, relative to For locally advanced resectable disease (T3-4a, N0-1; or any T, N2-3), surgery (HR, 1.66; 95% CI, 1.26–2.18; P < .001), and this difference 3 treatment options are recommended (see the NCCN Guidelines for was not statistically significant for patients with p16-positive disease Cancer of the Oropharynx), in addition to enrollment in multimodality (HR, 1.33; 95% CI, 0.94–1.87; P = .114). There may also be an clinical trials. The 3 options are: 1) concurrent systemic therapy/RT association between HPV status and survival in patients with recurrent (surgery is used for managing residual or recurrent disease);155 2) or metastatic disease.19,22,346,347 transoral or open resection of the primary and neck (with appropriate adjuvant therapy [systemic therapy/RT or RT]); or 3) induction Since patients with locally advanced HPV-positive oropharyngeal chemotherapy (category 3) (followed by RT or systemic therapy/RT), cancer may live longer, late toxicity and quality of life are concerns for although panel members had a major disagreement for induction these patients.348,349 Therefore, consensus is increasing that HPV status 71,74,334 therapy. should be used as a stratification factor or should be addressed in

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

separate trials (HPV-related vs. unrelated disease) for which patients this review included unplanned subgroup analyses, the grouping of with oropharyngeal cancer are eligible.350-352 Some clinicians have multiple H&N subsites, inconsistent quantitative reporting and lack of recently suggested that less-intense treatment may be adequate for reporting on tumor and lymph node classification, treatment effect sizes, HPV-positive oropharyngeal cancers (ie, deintensification)29; however, multivariable analyses, and quality of life outcomes. Therefore, the the available data supporting this assertion are limited by retrospective investigators who carried out this review argued that these trials lack the analyses, variability in HPV testing method used, and short follow-up generalizability necessary to rationalize the use of adjuvant systemic periods.29,348,353,354 Deintensification treatment protocols for HPV- therapy/RT in patients with p16-positive disease. associated locally advanced oropharyngeal cancer are being investigated in ongoing clinical trials. Strategies under active Recent retrospective studies have not observed a statistically significant investigation include reducing or using response-stratified RT dose, association between extracapsular spread and survival in patients with 27,350,359-362 using RT alone versus chemoradiation, using less invasive surgical HPV-positive oropharyngeal cancer. For example, a study of procedures such as transoral robotic surgery, using sequential systemic 220 patients with p16-positive oropharyngeal cancer who received therapy/RT, and using immunotherapy and targeted therapy agents surgical resection with or without adjuvant treatment showed that the such as cetuximab.348,349,355 The ECOG-ACRIN phase II E1308 trial, in presence of five or more metastatic nodes is associated with disease which patients with stage III-IV HPV16 and/or p16-positive recurrence and survival, but extracapsular spread was not significantly 361 oropharyngeal cancer (N = 80) received induction chemotherapy associated with outcomes in this sample. Recent studies of patients followed by reduced-dose RT and weekly cetuximab, recently reported with p16-positive oropharyngeal cancer treated with surgery show that results, showing that RT deintensification may result in equivalent or soft tissue metastasis may be associated with poor survival outcomes, 27,363 similar response in selected patients, compared to full-dose RT.356 especially in patients with T3-T4 disease. These results suggest that patients with p16-positive disease with extracapsular spread could The panel currently recommends adjuvant systemic therapy/RT in potentially be treated differently than patients with p16-negative disease patients with squamous cell carcinoma of the oropharynx in the and extracapsular spread. presence of the adverse pathologic features of extracapsular nodal spread with (or without) positive mucosal margins. This Adjuvant systemic therapy/RT in patients with oropharyngeal cancer recommendation is primarily based on results from RTOG 9501 and who have extracapsular spread is recommended as a category 2A EORTC 22931.100,101,103 However, in a review of published data from option, based on a lack of high-quality, prospective clinical evidence these RCTs, it was noted that the panel’s recommendations are based and controversy. Adjuvant systemic therapy/RT remains a category 1 on studies that did not investigate the impact of HPV or p16 status.357 In recommendation for patients with other types of H&N cancer who have response to this review, the investigators from RTOG 9501 and EORTC extracapsular spread, including HPV-negative oropharynx cancer. 22931 pointed out that the prevalence of HPV-positive/p16-positive Deintensification treatment protocols for patients with HPV-related tumors was likely to be low in these trials.358 Other limitations noted in oropharyngeal cancer are currently being investigated (eg, NCT01154920, NCT01706939, NCT01302834, NCT01855451). Panel

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

members urge that patients with HPV-related cancers be enrolled in chemotherapy; systemic therapy/RT is a category 2B recommendation clinical trials evaluating biological and treatment-related after a partial response. questions.348,349,364 A summary of the data helps provide some perspective on the NCCN The Induction Chemotherapy Controversy Panel’s recommendations. Most randomized trials of induction Defining the role of induction chemotherapy in the management of chemotherapy followed by RT and/or surgery compared to locoregional locally or regionally advanced H&N cancers has generated considerable treatment alone, which were published in the 1980s and 1990s, did not discussion within the NCCN panel in recent years. The algorithm for the show an improvement in overall survival with the incorporation of management of advanced oropharyngeal cancer (see the NCCN chemotherapy.340 However, a change in the pattern of failure with less Guidelines for Cancer of the Oropharynx) illustrates the lack of distant metastases was noted in some studies.365 Also, a correlation consensus among NCCN Member Institutions despite the extensive was noted between response to induction chemotherapy and discussion. Thus, induction chemotherapy has a category 3 subsequent durable response to radiation.365,366 Thus, the concept recommendation (ie, major disagreement) for the management of both developed that in selected patients, induction chemotherapy could locally and regionally advanced oropharyngeal cancer (ie, T3-4a, N0-1, facilitate organ preservation, avoid morbid surgery, and improve overall any T, N2-3). However in other sites, category 2A and 2B quality of life of the patient even though overall survival was not recommendations for induction chemotherapy are common based on improved. Because total laryngectomy is among the procedures most the update from RTOG 91-11 (see Cancer of the Glottic Larynx, Cancer feared by patients,367 larynx preservation was the focus of initial studies. of the Supraglottic Larynx, Cancer of the Hypopharynx, Cancer of the Nasopharynx, Occult Primary, and Very Advanced H&N Cancer in the Two randomized studies—the Veterans Affairs (VA) Laryngeal Cancer NCCN Guidelines for Head and Neck Cancers).212 For selected patients Study Group trial in advanced laryngeal cancer and the EORTC trial with hypopharyngeal and laryngeal cancers less than T4a in extent (for predominantly in advanced hypopharynx cancer—established the role which total laryngectomy is indicated, if managed surgically), induction of induction cisplatin/5-FU chemotherapy followed by definitive RT in chemotherapy—used as part of a larynx preservation strategy—is responding patients as an alternative treatment to primary total category 2A. laryngectomy and postoperative radiation, offering potential larynx preservation without compromise in survival (see Cancer of the Larynx Panel members feel that induction chemotherapy should only be done and Cancer of the Hypopharynx in this Discussion).365,366 Yet even in in centers with expertise in these regimens because of challenges this setting, the role of induction chemotherapy decreased with time. associated with appropriate patient selection and management of Randomized trials and related meta-analyses indicated that concurrent treatment-related toxicities.335 Residual toxicity from induction systemic RT (with cisplatin being the best studied agent) offered chemotherapy may also complicate the subsequent delivery of definitive superior locoregional tumor control and survival compared to radiation RT or systemic therapy/RT. For laryngeal cancer, RT alone (category 1) alone,368-378 and shorter duration of therapy compared to induction is recommended after a complete or partial response with induction therapy followed by radiation. Meta-analyses reported that concurrent

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

systemic RT was more efficacious than an induction chemotherapy and cisplatin/5-FU were compared.383,384 A meta-analysis including five strategy.340,344 In the larynx preservation setting, Intergroup 91-11 RCTs (N = 1,772) showed that the TPF induction chemotherapy compared radiation alone, concurrent cisplatin/radiation, and induction regimen was associated with reduced risk of death (HR, 0.72; 95% CI, cisplatin/5-FU followed by radiation; all arms had surgery for 0.63–0.83; P < .001) and greater reductions in progression (HR, 0.78; relapsed/refractory disease. The concurrent arm had the highest larynx 95% CI, 0.69–0.87; P < .001), locoregional failure (HR, 0.79; 95% CI, preservation rate (see Cancer of the Larynx in this Discussion).379 A 0.66–0.94; P = 0.007), and distant failure (HR, 0.63; 95% CI, 0.45–0.89; long-term follow-up of 91-11 confirmed that concomitant systemic P = 0.009), compared with cisplatin plus 5-FU.385 therapy/RT improved the larynx preservation rate and that induction chemotherapy was not superior to RT alone.212 However, overall Whether adding induction chemotherapy to concurrent chemoradiation survival did not differ among the treatment arms. results in a clear advantage in overall survival continues to be unclear.337,386,387 Both the DeCIDE and the PARADIGM trials did not Nonetheless, interest in the role of induction chemotherapy endures for convincingly show a survival advantage with the incorporation of a few reasons. Advances in surgery, RT, and concurrent systemic induction chemotherapy.386,387 In patients with stage III or IV squamous therapy/RT have yielded improvements in local/regional control; thus, cell H&N cancers, a randomized phase II study compared induction the role of distant metastases as a source of treatment failure has TPF followed by concurrent cisplatin/5-FU with RT versus concurrent increased and induction chemotherapy allows greater drug delivery for cisplatin/5-FU with RT alone. A higher radiologic complete response this purpose.380,381 Clinicians have increasing concern regarding the rate was reported with the incorporation of induction chemotherapy.388 long-term morbidity of concurrent systemic therapy/RT, and thus have Results from a larger follow-up study suggest a survival advantage and increasing interest in exploring alternative approaches that might have a are currently reported in an abstract.389 The phase II ECOG-ACRIN trial more favorable side-effect profile.382 Finally, a more effective triplet (E2303) showed promising results in terms of primary site response and chemotherapy regimen has been identified for induction chemotherapy survival for cetuximab, paclitaxel, and carboplatin as induction compared to the standard cisplatin/5-FU used in induction trials of the chemotherapy, followed by systemic therapy/RT with the same drug 1980s and 1990s, and in the related meta-analyses. Three phase III regimen in patients with stage III or IV squamous cell H&N cancers (N = trials compared induction cisplatin plus infusional 5-FU with (or without) 74),390 but the incremental benefit of induction chemotherapy requires the addition of a taxane (docetaxel or paclitaxel) followed by the same further validation using randomized design. locoregional treatment. Results showed significantly improved outcomes (response rates, DFS, or overall survival depending on the After a complete or partial response with induction chemotherapy for trial) for patients in the 3-drug induction group compared to those patients with laryngeal cancer, RT alone is recommended (category 212 receiving 2 drugs (cisplatin plus 5-FU).338,339,342,343 A randomized phase 1); systemic therapy/RT is a category 2B recommendation after a 383,384,391 III trial in the larynx preservation setting similarly showed superior larynx partial response (see NCCN Guidelines for Cancer of the Glottic preservation outcome when induction docetaxel/cisplatin/5-FU (TPF) Larynx, Cancer of the Supraglottic Larynx). After induction chemotherapy, panel members agree that weekly cetuximab or

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

carboplatin are reasonable agents to use with concurrent radiation.386,392- subclinical disease, consistent with the fractionation schedule used for 394 Of note, investigators in the DeCIDE trial used the combination of these patients in RTOG 0615.112 Moderate acceleration of treatment is docetaxel/hydroxyurea/5-FU with RT after induction chemotherapy in acceptable in patients with early-stage oropharyngeal cancer.398 this setting.387 Because of toxicity concerns, high-dose cisplatin (100 mg/m2 every 21 days × 3) is not recommended after induction Follow-up/Surveillance cisplatin-based chemotherapy.337,393 Thus, this highlights concerns that Recommendations for surveillance are provided in the algorithm (see any efficacy gains of induction may be offset by the use of better Follow-up Recommendations in the NCCN Guidelines for Head and tolerated—but potentially less effective—concurrent regimens or poorer Neck Cancers). patient compliance with the radiation-based part of treatment. Because of these uncertainties, enrollment of patients in appropriate clinical trials Cancer of the Hypopharynx is particularly encouraged. Outside of a clinical trial, proceeding directly The hypopharynx extends from the superior border of the hyoid bone to to concurrent systemic RT—high-dose cisplatin preferred—is the lower border of the cricoid cartilage and is essentially a muscular, considered the gold standard by many NCCN Panel Members in lined tube extending from the oropharynx to the cervical esophagus. For several settings (see Principles of Systemic Therapy in the NCCN staging purposes, the hypopharynx is divided into 3 areas: 1) the Guidelines for Head and Neck Cancers).100-103,368,395 When induction pyriform sinus (the most common site of cancer in the hypopharynx); 2) chemotherapy is used, data show that the addition of a taxane to the lateral and posterior pharyngeal walls; and 3) the postcricoid area. cisplatin/5-FU, of which TPF is the most extensively studied, is more efficacious than cisplatin/5-FU.385 Therefore, when used as induction Workup and Staging chemotherapy for oropharyngeal cancer, this regimen is a category 1 A multidisciplinary consultation is encouraged. Accurate staging (see recommendation. Paclitaxel, cisplatin, and 5-FU is also an option for Table 2) depends on a complete H&N examination coupled with induction chemotherapy.338 appropriate studies (see Workup in the NCCN Guidelines for Cancer of the Hypopharynx).31 At the time of diagnosis, approximately 60% of Radiation Therapy Fractionation patients with cancer of the hypopharynx have locally advanced disease Standard conventional fractionation is preferred when RT is used with spread to regional nodes. Furthermore, autopsy series have shown definitively for T1-2, N0 tumors. Altered fractionation is appropriate for a high rate of distant metastases (60%) involving virtually every selected T1-2, N1 tumors, particularly if concurrent systemic therapy is organ.399 For patients with cancer of the hypopharynx, the prognosis not used. The recommended schedules are shown in the algorithm (see can be quite poor despite aggressive combined modality treatment. Principles of Radiation Therapy in the NCCN Guidelines for Cancer of the Oropharynx). IMRT may be useful for decreasing toxicity.396,397 A Treatment fractionation schedule of 69.96 Gy at 2.12 Gy/fraction daily (Monday– Patients with resectable disease are divided into 2 groups based on the Friday) for 6 to 7 weeks is recommended for patients with high-risk indicated surgical options: 1) those with early-stage cancer (most T1,

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

N0; selected T2, N0) amenable to larynx-preserving (conservation) of the pyriform sinus (152 patients) and aryepiglottic fold (42 patients), surgery; and 2) those with advanced resectable cancer (T1, N+; T2-4a, excluding patients with T1 or N2c disease. Patients were randomly any N) requiring (amenable to) pharyngectomy with total or partial assigned either to laryngopharyngectomy and postoperative RT, or to laryngectomy. The surgery and RT options for the former group (see the systemic therapy with cisplatin and 5-FU for a maximum of 3 cycles, NCCN Guidelines for Cancer of the Hypopharynx) represent a followed by definitive RT. In contrast to a similar approach used for consensus among the panel members. laryngeal cancer, a complete response to induction chemotherapy was required before proceeding with definitive RT. The published results Patients with more advanced disease (defined as T1, N+; T2-3, any showed equivalent survival, with median survival duration and a 3-year N)—for whom the indicated surgical option is partial or total survival rate of 25 months and 43%, respectively, for the surgery group laryngopharyngectomy—may be managed with 3 approaches (see the versus 44 months and 57%, respectively, for the induction NCCN Guidelines for Cancer of the Hypopharynx) in addition to chemotherapy group.365 A functioning larynx was preserved in 42% of enrollment in multimodality clinical trials: 1) induction chemotherapy patients who did not undergo surgery. Local or regional failure rates did followed by definitive RT (category 1 for RT) if a complete response was not differ between the surgery-treated patients and 365 achieved at the primary site or followed by other options depending chemotherapy-treated patients, although the chemotherapy recipients on the response; 2) surgery with neck dissection and postoperative did show a significant reduction in distant metastases as a site of first radiation or chemoradiation as dictated by pathologic risk features; or 3) failure (P = .041). concurrent systemic therapy/RT (see the NCCN Guidelines for Cancer of the Hypopharynx). When using concurrent systemic therapy/RT, the For induction chemotherapy as part of a larynx preservation strategy, preferred systemic agent is high-dose cisplatin (category 1) (see inclusion of only patients with the specified TN stages is recommended. Principles of Systemic Therapy in the NCCN Guidelines for Head and Success on larynx preservation with an induction chemotherapy Neck Cancers). Fractionation for RT is discussed in the algorithm (see strategy is best established for patients who had a complete response Principles of Radiation Therapy in the NCCN Guidelines for Cancer of to induction therapy at the primary site and stable or improved disease the Hypopharynx). A fractionation schedule of 69.96 Gy at 2.12 in the neck. A randomized trial showed that an alternating regimen of Gy/fraction daily (Monday–Friday) for 6 to 7 weeks is recommended for cisplatin/5-FU with RT yielded larynx preservation, progression-free patients with high-risk subclinical disease, consistent with the interval, and overall survival rates equivalent to those obtained with fractionation schedule used for these patients in RTOG 0615.112 Given induction platinum/5-FU followed by RT.400 Given available randomized the functional loss resulting from this surgery and the poor prognosis, data demonstrating the superiority of TPF compared with PF for participation in multimodality clinical trials is emphasized. induction chemoradiation, the triplet is now recommended as induction for this approach.383,384 The recommendation of the induction chemotherapy/definitive RT option is based on an EORTC randomized trial.365 This trial enrolled 194 As noted in the algorithm, surgery is recommended if less than a partial eligible patients with stage II to IV resectable squamous cell carcinoma response (or a partial response) occurs after induction chemotherapy

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

(see the NCCN Guidelines for Cancer of the Hypopharynx). The nature important. The prognostic significance of histology is still controversial. of the operation will depend on the stage and extent of the tumor. RT was the standard treatment for all stages of this disease, until the Partial laryngeal surgery may still be considered, although most patients mid-1990s, when trial data showed improved survival for locally will require total laryngectomy. In this situation, or when primary surgery advanced tumors treated with concurrent RT and cisplatin.395 is the selected management path, postoperative chemotherapy/RT is recommended (category 1) for the adverse pathologic features of Workup and Staging extracapsular nodal spread and/or positive mucosal margin. For other The workup of nasopharyngeal cancer includes a complete H&N risk features, clinical judgment should be used when deciding to use RT examination and other studies (see the NCCN Guidelines for Cancer of alone or when considering adding chemotherapy to RT (see the NCCN the Nasopharynx). These studies are important to determine the full Guidelines for Cancer of the Hypopharynx). Severe late toxicity appears extent of tumor in order to assign stage appropriately and to design to be associated with the amount of RT.382 Options for patients with T4a, radiation ports that will encompass all the disease with appropriate any N disease include: 1) surgery plus neck dissection followed by doses. Multidisciplinary consultation is encouraged. The 2010 AJCC adjuvant systemic therapy/RT or RT; 2) multimodality clinical trials; 3) staging classification (7th edition) is used as the basis for treatment induction chemotherapy (category 3); or 4) systemic therapy/RT recommendations (see Table 2).31 (category 3) (see the NCCN Guidelines for Cancer of the Hypopharynx). Workup for nasopharyngeal cancer may include Epstein–Barr Virus Follow-up/Surveillance (EBV)/DNA testing, particularly in the presence of nonkeratinizing and 406-408 Recommendations for surveillance are provided in the algorithm (see undifferentiated histology. Some studies have shown that high Follow-up Recommendations in the NCCN Guidelines for Head and levels of plasma EBV DNA are associated with significantly poorer 409-411 Neck Cancers). disease outcomes following RT or chemoradiation. A meta- analysis including 13 studies showed that plasma EBV DNA levels Cancer of the Nasopharynx assessed at pre-treatment were associated with mortality (HR, 2.81; Carcinoma of the nasopharynx is uncommon in the United States. 95% CI, 2.44–3.24; P < .001) and distant metastasis (HR, 3.89; 95% CI, Among H&N cancers, it has among the highest propensity to 3.39–4.47; P < .001), though these studies were significantly metastasize to distant sites. Nasopharyngeal cancer also poses a heterogeneous (P = .03), and subgroup analyses were not statistically 412 significant risk for isolated local recurrences after definitive radiation significant. A retrospective study including 584 patients showed that (without systemic therapy) for locally advanced disease.401-404 Regional pre-treatment plasma EBV DNA levels were significantly associated recurrences are uncommon in this disease, occurring in only 10% to with T and N classifications, but not DFS, overall survival, locoregional 413 19% of patients.404,405 The NCCN Guidelines for the evaluation and relapse-free survival, or distant metastasis-free survival. PCR is a 414 management of carcinoma of the nasopharynx attempt to address risk sensitive method for evaluating EBV DNA load in plasma. Testing for both local and distant disease. Stage is accepted as prognostically methods for detection of EBV in tumor tissue include ISH for EBV-

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

encoded RNA (EBER)415 and immunohistochemical staining for distant recurrence rates. A similar randomized study conducted in LMP1.416 ISH for EBER tends to be a more sensitive testing method of Singapore, which was modeled after the Intergroup treatment regimen, carcinomas, relative to LMP1 IHC staining.417 continued to show the benefit of adding chemotherapy to RT. After combined chemotherapy and radiation, adjuvant chemotherapy was Treatment also given in this trial.422 In addition, the administration of the cisplatin Patients with T1, N0, M0 nasopharyngeal tumors should be treated with dose was spread out over several days, and this regimen appeared to definitive RT alone and elective RT to the neck (see the NCCN reduce toxicity while still providing a beneficial antitumor effect. Guidelines for Cancer of the Nasopharynx). For early-stage cancer in this setting, radiation doses of 66 to 70.2 Gy given with standard Another phase III randomized trial showed that concurrent fractions are necessary for control of the primary tumor and involved chemotherapy/RT (using weekly cisplatin) increased survival when 423 lymph nodes (see Principles of Radiation Therapy in the NCCN compared with RT alone. Five-year overall survival was 70% for the Guidelines for Cancer of the Nasopharynx). The local control rate for chemotherapy/RT group versus 59% for the RT group. A randomized these tumors ranges from 80% to 90%, whereas T3-4 tumors have a trial compared chemotherapy/RT using cisplatin versus carboplatin and control rate of 30% to 65% with RT alone.418,419 For patients with high- found that the 3-year overall survival rates were similar (78% vs. 394 risk subclinical disease, doses greater than 70 Gy may be used, with a 79%). Results of a phase III randomized trial showed that oxaliplatin modified fractionation (eg, <2.0 Gy/fraction) for at least part of treatment with concurrent RT had greater 5-year OS (73.2% vs. 60.2%, P = to minimize toxicity. A fractionation schedule of 69.96 Gy at 2.12 0.028) and metastasis-free survival (74.7% vs. 63.0%, P = 0.027) in Gy/fraction daily (Monday–Friday) for 6 to 7 weeks is recommended for patients with locally advanced nasopharyngeal cancer, relative to 424 patients with high-risk subclinical disease, consistent with the patients who received RT alone (N = 115). However, the NCCN fractionation schedule used for these patients in RTOG 0615.112 Guidelines recommend cisplatin for systemic therapy/RT in patients who do not have a contraindication to the drug, because more data from Recent meta-analyses showed that concurrent systemic therapy/RT randomized trials support the use of cisplatin in this setting (see significantly improves outcomes in patients with locoregionally Principles of Systemic Therapy in the NCCN Guidelines for Head and advanced nasopharyngeal cancer.420,421 The combination of RT and Neck Cancers).395,423 concurrent platinum-based systemic therapy followed by adjuvant cisplatin/5-FU has been shown to increase the local control rate from Results of a network meta-analysis (including 20 trials and 5,144 54% to 78%. The Intergroup trial 0099, which randomly assigned patients) showed that the addition of adjuvant chemotherapy to patients to chemotherapy plus EBRT versus external radiation alone, chemoradiation is associated with greater PFS, compared to 425 closed early when an interim analysis disclosed a significant survival chemoradiation alone (HR, 0.81; 95% CI, 0.66–0.98). However, a 426 advantage favoring the combined chemotherapy and radiation group.395 systematic review of 25 RCTs and a phase III randomized trial The addition of chemotherapy also decreased local, regional, and comparing concurrent chemotherapy/RT with (or without) adjuvant cisplatin/5-FU427 showed that adjuvant systemic therapy does not

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

significantly improve survival following systemic therapy/RT. Concurrent disease in the neck and a complete response at the primary should chemoradiotherapy (cisplatin) with adjuvant systemic therapy for undergo a neck dissection. nasopharyngeal cancer is a recommended treatment option. Concurrent chemoradiotherapy (cisplatin) without adjuvant systemic therapy is a For patients who present with metastatic disease or recurrent or category 2B recommendation. For both T1, N1-3; and for T2-T4, any N persistent nasopharyngeal cancer, see the NCCN Guidelines for Very lesions, multimodality clinical trials are preferred. However, the NCCN Advanced Head and Neck Cancer. Guidelines also recommend concurrent systemic therapy (cisplatin) plus Follow-up/Surveillance RT, followed or not followed by adjuvant cisplatin/5-FU (see the NCCN Guidelines for Cancer of the Nasopharynx).395,423,427 If using adjuvant Recommendations for surveillance are provided in the algorithm (see systemic therapy, adjuvant carboplatin/5-FU is also an option; however, Follow-up Recommendations in the NCCN Guidelines for Head and this recommendation is a category 2B option because there is less Neck Cancers). Since the nasopharynx may be inaccessible to clinical experience using carboplatin in this setting and because the Chen et al examination, then imaging may be necessary. The clinical benefit of study suggests that it is reasonable not to use adjuvant systemic EBV DNA monitoring is currently uncertain but may be considered therapy (see Principles of Systemic Therapy in the NCCN Guidelines for (category 2B). Head and Neck Cancers).427,428 The panel is interested in further Cancer of the Larynx follow-up to the Chen et al study to clarify the role of adjuvant systemic therapy in this setting.427 The larynx is divided into 3 regions: supraglottis, glottis, and subglottis. The distribution of cancers is as follows: 30% to 35% in the supraglottic Induction chemotherapy (category 3) (followed by systemic therapy/RT) region, 60% to 65% in the glottic region, and 5% in the subglottic is also recommended for patients with nasopharyngeal cancer with region. The incidence and pattern of metastatic spread to regional either T1, N1-3 or T2-T4, any N lesions (see the NCCN Guidelines for nodes vary with the primary region. More than 50% of patients with Cancer of the Nasopharynx). Panel members had widespread supraglottic primaries present with spread to regional nodes because of disagreement regarding whether induction chemotherapy is appropriate, an abundant lymphatic network that crosses the midline. Bilateral which is reflected in the category 3 recommendation (see The Induction adenopathy is not uncommon with early-stage supraglottic primaries. Chemotherapy Controversy in this Discussion). Several Thus, supraglottic cancer is often locally advanced at diagnosis. In induction/sequential chemotherapy options are recommended in the contrast, the lymphatic drainage of the glottis is sparse and early-stage algorithm for nasopharyngeal cancer (see Principles of Systemic primaries rarely spread to regional nodes. Because hoarseness is an Therapy in the NCCN Guidelines for Head and Neck early symptom, most glottic cancer is early stage at diagnosis. Thus, Cancers).339,394,423,429,430 Docetaxel/cisplatin (category 2B) is also an glottic cancer has an excellent cure rate of 80% to 90%. Nodal option.431 Although an unusual occurrence, a patient with residual involvement adversely affects survival rates.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Workup and Staging margins. For select patients with T1-3, N+ supraglottic disease, re- The evaluation of the patient to determine tumor stage is similar for resection may be attempted if negative margins are feasible and can be glottic and supraglottic primaries (see Cancer of the Glottic Larynx and achieved without total laryngectomy, and if re-resection has the Cancer of the Supraglottic Larynx in the NCCN Guidelines for Head and potential to change the indication for adjuvant systemic therapy/RT. Neck Cancers). Multidisciplinary consultation is critical for both sites Based on the update of RTOG 95-01, the panel deleted the because of the potential for loss of speech and, in some instances, for recommendation for consider [adjuvant] systemic therapy/RT for swallowing dysfunction (see Principles of Nutrition: Management and patients with T2, N0 glottic cancer with either other risk features or 102 Supportive Care in the NCCN Guidelines for Head and Neck Cancers). positive margins. The long-term update of RTOG 95-01 reported that The 2010 AJCC staging classification (7th edition) for laryngeal primary locoregional control and DFS were not improved with the addition of tumors is determined by the number of subsites involved, vocal cord adjuvant systemic therapy/RT when compared with RT alone in patients mobility, and the presence of metastases (see Table 3).31 with 2 or more involved lymph nodes. However, an unplanned subgroup analysis did show improvement in locoregional control and DFS in Treatment patients with extracapsular spread and/or positive margins. In the NCCN Guidelines, the treatment of patients with laryngeal cancer Resectable, advanced-stage glottic and supraglottic primaries are is divided into 2 categories: 1) tumors of the glottic larynx; or 2) tumors usually managed with a combined modality approach (see Cancer of of the supraglottic larynx. Subglottic cancer is not discussed, because it the Glottic Larynx and Cancer of the Supraglottic Larynx in the NCCN is so uncommon. Guidelines for Head and Neck Cancers). If treated with primary surgery, For patients with carcinoma in situ of the larynx, recommended total laryngectomy is usually indicated, although selected cases can be treatment options include: 1) endoscopic removal (ie, stripping, laser), managed with conservation surgical techniques that preserve vocal which is preferred; or 2) RT.432,433 For early-stage glottic or supraglottic function. Pulmonary function tests should be considered before surgery. cancer, surgery or RT have similar effectiveness434 (see Cancer of the If total laryngectomy is indicated but laryngeal preservation is desired, Glottic Larynx and Cancer of the Supraglottic Larynx in the NCCN concurrent systemic therapy/RT is recommended.212,379 When using Guidelines for Head and Neck Cancers), though the quality of studies systemic therapy/RT, high-dose cisplatin (category 1) is preferred (at comparing the effectiveness of RT and surgery in early laryngeal cancer 100 mg/m2 on days 1, 22, and 43).212 Induction chemotherapy with is low.435 The choice of treatment modality depends on anticipated management based on response is an option for all but T1-2, N0 glottic functional outcome, the patient’s wishes, reliability of follow-up, and cancer. Based on the long-term update of RTOG 91-11, panel members general medical condition.436 added an option for the use of induction chemotherapy when patients Adjuvant treatment depends on the presence (or absence) of adverse require (are amenable to) total laryngectomy (see The Induction 212 features. Adjuvant treatment for select patients with T1-2, N0 Chemotherapy Controversy in this Discussion). The panel revised the supraglottic cancer may include re-resection if there are positive recommendations for the use of induction chemotherapy from category

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

3 to category 2A for T3, N2-3 when patients require total laryngectomy control) rate of 88% for concurrent RT with cisplatin, compared to 74% (see The Induction Chemotherapy Controversy in this Discussion and for induction chemotherapy and 69% for RT alone; 2) no significant the NCCN Guidelines for Cancer of the Glottic Larynx and Cancer of difference in laryngeal preservation between induction and RT alone Supraglottic Larynx).212 Definitive RT (without systemic therapy) is an treatments; and 3) similar survival for all treatment groups. These option for patients with T3, N0-1 disease who are medically unfit or R91-11 results changed the recommended treatment to concurrent RT refuse systemic therapy (see Cancer of the Glottic Larynx and Cancer and systemic therapy (cisplatin preferred [category 1]) for achieving of the Supraglottic Larynx in the NCCN Guidelines for Head and Neck laryngeal preservation for T3, N0 and T4a, N0 supraglottic cancers and Cancers). Surgery is reserved for managing the neck as indicated, for for most T3, any N glottic cancers.379 Long-term follow-up (10 years) of those patients whose disease persists after systemic therapy/RT or RT, R91-11 indicates that laryngeal preservation continues to be better (ie, or for those patients who develop a subsequent locoregional recurrence statistically different) with concurrent cisplatin/RT when compared with (see Post-chemoradiation or RT Neck Evaluation in Principles of either induction chemotherapy or RT alone.212 Overall survival was not Surgery in the NCCN Guidelines for Head and Neck Cancers). statistically different for all treatment groups; there was more non-cancer–related mortality among patients treated with concurrent The NCCN recommendations for managing locally advanced, cisplatin/RT. resectable glottic and supraglottic cancers (in which total laryngectomy is indicated but laryngeal preservation is desired) with concurrent For patients with glottic and supraglottic T4a tumors, the recommended cisplatin and radiation are based on Intergroup trial R91-11.212,379 treatment approach is total laryngectomy with thyroidectomy and neck Concurrent RT and systemic therapy (eg, cisplatin 100 mg/m2 preferred dissection as indicated (depending on node involvement) followed by [category 1]) is the recommended option for achieving laryngeal adjuvant treatment (RT, or systemic therapy/RT may be considered)437 preservation.212,379 (see Cancer of the Glottic Larynx, Cancer of the Supraglottic Larynx, and Principles of Surgery in the NCCN Guidelines for Head and Neck R91-11 was a successor trial to the VA trial and compared 3 Cancers). For patients with glottic T4a larynx cancer, postoperative non-surgical regimens: 1) induction cisplatin/5-FU followed by RT observation is an option for highly selected patients with good-risk (control arm and identical to that in the VA trial); 2) concurrent RT and features (eg, indolent histopathology). For selected patients with T4a 2 high-dose cisplatin 100 mg/m days 1, 22, and 43; and 3) RT alone. RT tumors who decline surgery, the NCCN Panel recommends: 1) was uniform in all 3 arms (70 Gy/7 weeks, 2 Gy/fraction), as was the considering concurrent chemoradiation; 2) clinical trials; or 3) induction option of surgery (including total laryngectomy) for relapsed/refractory chemotherapy with additional management based on response.212,379 disease in all arms. Patients with stage III and IV (M0) disease were eligible, excluding T1 primaries and high-volume T4 primaries (tumor Follow-up/Surveillance extending more than 1 cm into the base of the tongue or tumor Recommendations for surveillance are provided in the algorithm (see penetrating through cartilage). The key findings of the R91-11 trial were: Follow-up Recommendations in the NCCN Guidelines for Head and 1) a statistically significant higher 2-year laryngeal preservation (local

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Neck Cancers). Follow-up examinations in many of these patients may Guidelines for Soft Tissue Sarcoma and Non-Hodgkin’s Lymphoma, need to be supplemented with serial endoscopy or high-resolution, available at www.NCCN.org).443,444 advanced radiologic imaging techniques because of the scarring, edema, and fibrosis that occur in the laryngeal tissues and neck after Ethmoid Sinus Tumors high-dose radiation. Patients with early-stage ethmoid sinus cancer are typically asymptomatic. These neoplasms are often found after a routine nasal Paranasal Tumors (Maxillary and Ethmoid Sinus polypectomy or during the course of a nasal endoscopic procedure. For Tumors) a patient with gross residual disease who has had a nasal endoscopic Tumors of the paranasal sinuses are rare, and patients are often surgical procedure, the preferred treatment is complete surgical asymptomatic until late in the course of their disease. Tumors of the resection of the residual tumor. This procedure often entails an anterior maxillary sinus are more common than those of the ethmoid sinus or craniofacial resection to remove the cribriform plate and to ensure clear nasal cavity.31 Note that the workup for patients with suspected surgical margins. Nodal involvement is rare in ethmoid sinus tumors, paranasal sinus tumors includes a complete H&N CT with contrast or and lymph node metastasis is associated with poor prognosis.445 MRI with contrast; dental/prosthetic and multidisciplinary consultations Patients with ethmoid sinus cancer who have N+ neck disease should are recommended if clinically indicated. FDG-PET/CT may be undergo neck dissection with appropriate risk-based adjuvant therapy. considered in the workup of patients with clinically apparent stage III or IV disease. Most patients with ethmoid sinus cancer present after having had an incomplete resection. The patient who is diagnosed after incomplete Although the most common histology for these tumors is squamous cell resection (eg, polypectomy)—and has no documented residual disease carcinoma, multiple histologies have been reported including on physical examination, imaging, and/or endoscopy—should be adenocarcinoma, esthesioneuroblastoma (also known as olfactory treated with surgical resection if feasible (see the NCCN Guidelines for neuroblastoma), minor salivary gland tumors, and undifferentiated Ethmoid Sinus Tumors). If no adverse pathologic factors are found, this carcinoma (eg, sinonasal undifferentiated carcinoma [SNUC], small cell, treatment may obviate the need for postoperative RT in T1 patients only or sinonasal neuroendocrine carcinoma [SNEC]).438-441 Locoregional (category 2B). However, RT may be used as definitive treatment in control and incidence of distant metastasis are dependent on T stage, N patients if pre-biopsy imaging studies and nasal endoscopy show that stage, and tumor histology.442 However, T stage remains the most the superior extent of the disease does not involve the skull base. For reliable predictor of survival and local regional control (see Table 4).31 patients with high risk subclinical disease, doses greater than 70 Gy MM also occurs in the paranasal sinus region, nasal cavity, and oral may be used, with a modified fractionation (eg, less than 2.0 cavity (see Mucosal Melanoma of the Head and Neck in this Discussion Gy/fraction) for at least part of treatment to minimize toxicity. Note that and the NCCN Guidelines for Mucosal Melanoma). Biopsy results may extensive revisions were made to the radiation guidelines (see also indicate that patients have sarcoma or lymphoma (see the NCCN Principles of Radiation Therapy in the NCCN Guidelines for Ethmoid

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Sinus Tumors; see also Head and Neck Radiation Therapy in this Very Advanced Head and Neck Cancers Discussion). Very advanced H&N cancers include: 1) newly diagnosed locally advanced T4b (M0); 2) newly diagnosed unresectable nodal disease; 3) Systemic therapy should be part of the overall treatment for patients metastatic disease at initial presentation (M1); 4) recurrent or persistent with SNUC, small cell, or SNEC histologies.446-455 Surgery and RT have disease; or 5) patients unfit for surgery. The treatment goal is cure for been used to treat patients with esthesioneuroblastomas; systemic patients with newly diagnosed but unresectable disease (see comments therapy has also been incorporated into the local/regional treatment.454- about unresectable disease in the section on Head and Neck Surgery in 460 Long-term follow-up is necessary for esthesioneuroblastomas, this Discussion). For the recurrent disease group, the goal is cure (if because recurrence can even occur after 15 years.454,461,462 surgery or radiation remains feasible) or palliation (if the patient has Maxillary Sinus Tumors received previous RT and the disease is unresectable). For patients with metastatic disease, the goal is palliation or prolongation of life. Surgical resection for all T stages (except T4b, any N) followed by postoperative therapy remains a cornerstone of treatment for maxillary Treatment sinus tumors (see the NCCN Guidelines for Maxillary Sinus Participation in clinical trials is preferred for all patients with very Tumors).235,463-465 However, definitive RT or systemic therapy/RT is advanced H&N cancers. Combination regimens recommended by the recommended for T4b, any N, although this is a category 2B panel for recurrent, unresectable, or metastatic disease are as follows: recommendation for patients with T3-4a, N0 disease.466 Studies using 1) cisplatin/docetaxel/cetuximab (for non-nasopharyngeal cancer);471 2) IMRT have shown that it reduces the incidence of complications, such cisplatin/paclitaxel/cetuximab (for non-nasopharyngeal cancer);472,473 as radiation-induced ophthalmologic toxicity; however, the 5-year and 3) cisplatin/gemcitabine (for nasopharyngeal cancer).474 For the overall survival rate has not improved.190,235,467-470 Extensive revisions cisplatin/docetaxel/cetuximab regimen, the median PFS was 7.1 months were made to the radiation guidelines (see Principles of Radiation and overall survival was 15.3 months; 1-year overall survival was Therapy in the NCCN Guidelines for Maxillary Sinus Tumors; see also 58.6%. This newer taxane-based regimen has impressive overall Head and Neck Radiation Therapy in this Discussion). Participation in survival and is an option for patients with good PS. Carboplatin clinical trials is recommended for patients with malignant tumors of the combined with a taxane and cetuximab was also added as a treatment paranasal sinuses. option for recurrent, unresectable, or metastatic disease in 2017. Follow-up However, the preferred treatment option for recurrent, unresectable, or metastatic non-nasopharyngeal cancer is considered to be the regimen Recommendations for surveillance are provided in the algorithm (see from the EXTREME trial of cetuximab plus cisplatin/5-FU or Follow-up Recommendations in the NCCN Guidelines for Head and carboplatin/5-FU (category 1).475 Results from a trial that compared 5 Neck Cancers). different cisplatin-based regimens for nasopharyngeal cancer showed

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

that a cisplatin/gemcitabine regimen was effective although not better RT and cetuximab and 36.4% in patients who received RT alone (HR, than either cisplatin/5-FU or cisplatin/paclitaxel.474 0.73; 95% CI, 0.56–0.95; P = .018).477 However, in a report of secondary analyses from this trial including only patients with cancer or The treatment of patients with unresectable, persistent, recurrent, or the larynx or hypopharynx (n = 168), investigators failed to find a metastatic H&N cancers should be dictated, in large part, by the statistically significant difference between the two groups for laryngeal patient’s performance status (see the NCCN Guidelines for Very preservation, laryngectomy-free survival, and median overall survival.478 Advanced Head and Neck Cancers). Patients should be fully informed Nevertheless, trial results show that RT and cetuximab may provide a about the goals of treatment, cost of combination systemic therapy, therapeutic option for patients not considered medically fit for standard and potential for added toxicity. chemoradiotherapy regimens.

Newly Diagnosed Advanced Disease Other chemoradiation options (eg, carboplatin/5-FU [category 1]) are 104,150,151,368-374 Many randomized trials and meta-analyses of clinical also recommended by the NCCN Panel (see Principles of Systemic 340,375-378 trials show significantly improved overall survival, DFS, and local Therapy in the NCCN Guidelines for Head and Neck Cancers).145,479,480 control when a concomitant or alternating systemic therapy and A phase II randomized trial (N = 70) in which cisplatin and cetuximab, radiation regimen is compared with RT alone for advanced disease. All combined with RT, were compared showed that toxicity was combined chemoradiotherapy regimens are associated with mucosal significantly increased in patients randomized to receive cetuximab and toxicities, which require close monitoring of patients, ideally by a team RT, compared to patients randomized to receive cisplatin and RT.481 experienced in treating patients with H&N cancers. Limited data are Limited data are available comparing combination chemoradiation available comparing the efficacy of different chemoradiotherapy versus using a single agent concurrently with RT. Results of the regimens. High-dose cisplatin plus RT is effective and relatively easy to randomized phase III RTOG 0522 trial showed that the addition of administer and typically uses conventional fractionation at 2.0 Gy per cetuximab to cisplatin and RT did not significantly improve outcomes in fraction to 70 Gy or more in 7 weeks with single-agent cisplatin given patients with stage III or IV H&N cancer (N = 891).482 every 3 weeks at 100 mg/m2 (see Principles of Radiation Therapy in the NCCN Guidelines for Very Advanced Head and Neck Cancers).368 For patients with PS 0 or 1, the recommended treatment of newly diagnosed, very advanced disease is concurrent systemic therapy/RT Bonner et al randomly assigned 424 patients with locally advanced and (with high-dose cisplatin as the preferred [category 1] systemic measurable stage III to IV squamous cell carcinomas of the agent).368 Carboplatin/5-FU is another category 1 option.145 Cetuximab hypopharynx, oropharynx, and larynx to receive definitive RT with or with concurrent RT is a category 1 option for oropharynx, hypopharynx, 476 without cetuximab. Locoregional control and median overall survival and larynx; this regimen is a category 2B option for other squamous cell (49 months vs. 29.3 months, P = .03) were significantly improved in cancer sites of the H&N, based on results from Bonner et al.477 Other patients treated with RT and cetuximab compared to RT alone. Five- systemic therapy/RT options are listed in the guidelines (see Principles year overall survival in these patients was 45.6% in patients treated with of Systemic Therapy in the NCCN Guidelines for Head and Neck

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Cancers). The NCCN panel had a major disagreement regarding trials assessing a cisplatin-based combination regimen (such as whether induction chemotherapy (eg, TPF) followed by RT or cisplatin plus 5-FU) versus single-agent therapy with cisplatin, 5-FU, or chemoradiation should be used for patients with a PS of 0 or 1, which is methotrexate have shown significantly higher response rates, but no reflected in the category 3 recommendation (see also The Induction difference in overall survival, for the combination regimen.486,492,503-505 Chemotherapy Controversy in this Discussion).339,343 Other options for Historically, the median survival with systemic therapy is approximately patients with PS 2–3 are described in the algorithm (see the NCCN 6 months, and the 1-year survival rate is approximately 20%. Complete Guidelines for Very Advanced Head and Neck Cancers). response is associated with longer survival and, although infrequent, has been reported more often with combination regimens.492 A Metastatic Disease randomized phase III trial in patients with metastatic or recurrent H&N For patients with metastatic (M1) disease at initial presentation, cancers found no significant difference in survival when comparing palliative adjunctive measures include RT to areas of symptomatic cisplatin plus 5-FU with cisplatin plus paclitaxel.503 Activation of disease, analgesics, and other measures to control other manifestations epidermal growth factor receptor (EGFR) triggers a cascade of of disease spread (eg, hypercalcemia). Locoregional treatment prior to downstream intracellular signaling events important for regulation of beginning systemic therapy may be considered. Single agents and epithelial cell growth. Overexpression of EGFR and/or common ligands combination systemic therapy regimens are both used (see Principles of has been observed in greater than 90% of squamous cell carcinomas of Systemic Therapy in the NCCN Guidelines for Head and Neck the H&N. This finding has led to the development of EGFR inhibitors, 483 Cancers). Unless otherwise specified, regimens or single agents can such as the monoclonal antibody cetuximab and small molecule be used for either nasopharyngeal or non-nasopharyngeal cancer (see tyrosine kinase inhibitors (TKIs) (ie, erlotinib, gefitinib). Principles of Systemic Therapy in the NCCN Guidelines for Head and Neck Cancers). Response rates to single agents range from 15% to Data from phase II studies indicate that in the cisplatin-refractory 35%.472,484,485 Active and more commonly used single agents include setting, the single-agent response rate of cetuximab is about 12% to cisplatin, carboplatin, paclitaxel, docetaxel, 5-FU, methotrexate, 14%. Burtness et al487 compared cisplatin plus cetuximab versus capecitabine, cetuximab (for non-nasopharyngeal cancer), and cisplatin plus placebo as first-line treatment of recurrent disease; they gemcitabine (for nasopharyngeal cancer).472,483,486-501 For the 2017 reported a significant improvement in response rate with cetuximab update, vinorelbine was removed as a single agent option. (26% vs. 10%, respectively). A phase III randomized trial (EXTREME) of 442 patients with recurrent or metastatic squamous cell carcinoma Active combination regimens include: 1) cisplatin or carboplatin, plus found that cetuximab plus cisplatin/5-FU or carboplatin/5-FU improved 5-FU with cetuximab (for non-nasopharyngeal cancer only) (category median survival when compared to the standard systemic therapy 475 502,503 1); 2) cisplatin or carboplatin, plus a taxane; 3) cisplatin with doublet (10.1 vs. 7.4 months, P = .04).475 The response rate was also 487 cetuximab (for non-nasopharyngeal cancer only); or 4) cisplatin with improved with cetuximab (36% vs. 20% [P < .001]). In one randomized 492,503 5-FU. These combination regimens, on average, result in a trial, treatment with 2 different dosing schedules of gefitinib offered no doubling of response rates compared to single agents. Randomized

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

survival advantage compared to treatment with methotrexate.491 The management of patients with recurrent or persistent Available data for novel agents have not established them as nasopharyngeal cancer is described in the algorithm (see NCCN treatment options for recurrent or metastatic H&N cancers outside of a Guidelines for Very Advanced Head and Neck Cancer). Unless clinical trial.506,507 otherwise specified, regimens or single agents can be used for either nasopharyngeal or non-nasopharyngeal cancer (see Principles of For patients with nasopharyngeal cancer who present with metastatic Systemic Therapy in the NCCN Guidelines for Head and Neck disease, enrollment in a clinical trial is preferred. Other recommended Cancers). Combination therapy options include: 1) cisplatin or initial therapy options include either a platinum-based combination carboplatin with docetaxel or paclitaxel; 2) cisplatin/5-FU; 3) systemic therapy regimen or concurrent systemic therapy/RT; treatment cetuximab/carboplatin; and 4) gemcitabine with either cisplatin or depends on whether disease is localized or widespread (see NCCN vinorelbine.474,508-510 Results from a randomized phase III trial showed 395,423,428 Guidelines for Cancer of the Nasopharynx). For platinum-based that patients with recurrent or metastatic nasopharyngeal carcinoma (N combination systemic therapy, the different options are listed in the = 362) who received gemcitabine/cisplatin had a greater median PFS, algorithm (see Principles of Systemic Therapy in the NCCN Guidelines compared to patients who received cisplatin/5-FU (7.0 months vs. 5.6 394,429,430 for Head and Neck Cancers). months, respectively; HR, 0.55; 95% CI, 0.44–0.68; P < .001).511 For those who have failed platinum-based therapy, options are listed in the Recurrent or Persistent Disease algorithm (see Principles of Systemic Therapy in the NCCN Guidelines Surgery is recommended for resectable recurrent or persistent for Head and Neck Cancers).498,510 locoregional disease; adjuvant therapy depends on the risk factors (see the NCCN Guidelines for Very Advanced Head and Neck Cancers). If Reirradiation the recurrence is unresectable and the patient did not have prior RT, Reirradiation may be done in patients with recurrent H&N cancer, then RT with concurrent systemic therapy is recommended, depending using 3D-CRT, IMRT, PBT, or SBRT. A randomized phase III on the PS (see the NCCN Guidelines for Very Advanced Head and multicenter trial in France (N = 130) showed that reirradiation Neck Cancers). For patients with recurrent disease who are not combined with systemic therapy in patients with a resectable amenable to curative-intent radiation or surgery, the treatment approach recurrence improves DFS, compared to patients receiving only is the same as that for patients with metastatic disease; enrollment in a surgery (HR, 1.68; 95% CI, 1.13–2.50; P = .01).512 However, toxicity of clinical trial is preferred. Locoregional treatment may be considered in this regimen was considerable, with grade 3 of 4 acute toxicity the presence of distant metastasis with locoregional failure. Note that (mucositis/pharyngitis) in 28% of patients. the Principles of Radiation Therapy were extensively revised for patients with very advanced H&N cancers (see the NCCN Guidelines Advanced RT techniques may be used for reirradiation. A for Head and Neck Cancers; see also Head and Neck Radiation retrospective review of 227 patients who were treated at an NCCN Therapy in this Discussion). Member Institution showed that IMRT-based reirradiation of the H&N may be associated with local control and improved survival rates, but

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

toxicity rates were considerable, with adverse events grade 3 or higher Disease That Has Progressed on or After Platinum-containing occurring in 32% of patients at 2 years and 48% at 5 years.513 Use of Chemotherapy concurrent systemic therapy was associated with greater risk of Afatinib, a TKI, is a second-line systemic therapy option for non- toxicity. Use of particle therapy (eg, use of photon or proton therapy) nasopharyngeal persistent H&N cancer or cancer that has progressed may be associated with reduced mean dose to organs at risk.514 on or after platinum-containing chemotherapy (category 2B). This Retrospective studies show that PBT used for reirradiation may be addition was based on recently published results of the phase III LUX- associated with good outcomes (eg, 65%–84% overall survival, Head & Neck 1 RCT in which afatinib was compared to methotrexate improved locoregional control and freedom from distant metastasis) in patients with recurrent or metastatic H&N cancer who had 523 and acceptable toxicity.515,516 However, in one retrospective study, progressed on or after platinum-based therapy (N = 483). Patients three patients died (out of 60), possibly due to reirradiation-related randomized to receive afatinib had greater PFS, relative to patients effects.516 SBRT with or without cetuximab following surgery for randomized to receive methotrexate (2.6 months vs. 1.7 months; P = relapsed or refractory disease has been investigated in an institutional .03). Grade 3 or 4 adverse events reported in patients receiving report (N = 28).517 Rates for 1-year local control, distant control, DFS, afatinib were rash or acne (10%), diarrhea (9%), stomatitis (6%), and 523 and overall survival were 51%, 90%, 49%, and 64%, respectively, and fatigue (6%). Neutropenia was reported in one patient. Subgroup adverse events grade 3 or higher were rare. SBRT for reirradiation analyses from this trial showed that outcomes did not differ between should not be used in patients with circumferential carotid older and younger patients, indicating that afatinib may be safely used involvement, and dosing schedules may include 30 to 44 Gy in 5 in older adults, though the PFS benefit seemed to be most clear in the 524 fractions. HPV-negative group. A randomized phase II trial comparing afatinib to cetuximab in patients with recurrent or metastatic H&N cancer who The decision to treat with reirradiation should take into account had progressed on or after platinum-based therapy (N = 121) showed comorbidity, the toxicity of previous treatment methods, and the comparable response rates between the two drugs, though more 518-520 amount of time that has passed since previous treatment. patients randomized to receive afatinib discontinued treatment due to Treatment planning should take into account spinal cord limits, so that drug-related adverse events, relative to patients randomized to receive the safest maximum dose is delivered.518,521,522 Radiation volumes cetuximab (23% vs. 5%, respectively).525 should include known disease only; prophylactic treatment is not needed. There are currently knowledge gaps regarding appropriate Nivolumab, an anti-PD-1 antibody, was assessed in a phase III RCT use of irradiation, and patients should be encouraged to enroll in including 361 patients with recurrent H&N squamous cell cancer clinical trials.513,518 whose disease had progressed within 6 months following platinum- based chemotherapy.526 With a median follow-up of 5.1 (range 0–16.8) months, the overall survival was significantly greater in patients randomized to receive nivolumab, compared to patients randomized to receive standard second-line single-agent systemic therapy with either

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

methotrexate, docetaxel, or cetuximab (HR, 0.70; 97.73% CI, 0.51– and the PFS was 23%, with an overall response rate of 18%. 0.96; P = .01). One-year survival was also greater for patients who Observed responses appeared durable although the follow-up was received nivolumab, relative to patients who received standard therapy limited (median 9 months). By scoring both tumor and immune cells, (36.0% vs. 16.6%, respectively), and response rate was higher (13.3% the response rate in patients who were PD-L1-positive (≥1% vs. 5.8%, respectively), but median PFS was not significantly different expression) was significantly greater than in patients who were PD- between the two groups (2.0 months vs. 2.3 months, respectively; P = L1–negative (22% vs. 4%, respectively, P = .021), and responses 0.32). In prespecified exploratory analyses, the overall survival benefit were seen in both HPV-associated and non-HPV-associated disease. in the nivolumab-treated patients appeared to be confined to those Pembrolizumab was generally well-tolerated, with grade 3-4 toxicities patients with a tumor PD-L1 expression level of 1% or more (n = 149), reported in only 9% of patients, and no treatment-related deaths.527 (8.7 vs. 4.6 months, HR, 0.55; 95% CI, 0.36–0.83). In patients with tumor PD-L1 expression level less than 1% (n = 111), no overall The panel recommends nivolumab for patients with recurrent or survival advantage was demonstrated for the nivolumab-treated metastatic squamous cell H&N cancer who have progressed on or patients (5.7 vs. 5.8 months; HR, 0.89; 95% CI, 0.54–1.45). Grade 3 following platinum-based chemotherapy as a category 1 526 or 4 treatment-related adverse events occurred in 13.1% of patients recommendation based on high-quality evidence, while who received nivolumab, compared to 35.1% of patients who received pembrolizumab is recommended as a category 2a recommendation, 527,528 standard therapy. These results indicate that nivolumab prolongs based on results from nonrandomized trials. Despite the survival in patients with recurrent or metastatic squamous cell H&N ambiguities of PD-L1 testing and definitions, PD-L1 expression may cancer that has progressed after platinum-based chemotherapy, be associated with better outcomes from treatment with relative to patients who receive standard single-agent systemic immunotherapy for recurrent or metastatic squamous cell H&N cancer therapy. (ie, greater likelihood of response to pembrolizumab and greater survival benefit in response to nivolumab). Pembrolizumab, another anti-PD-1 antibody, was initially studied at a dose of 10 mg/kg given every two weeks in the squamous cell H&N Occult Primary Cancer cancer cohort of the KEYNOTE-012 trial.527 Clinical activity was When patients present with metastatic tumor in a neck node and no identified, and the possibility that responses could be durable was primary site can be identified after appropriate investigation, the tumor suggested. A lower, fixed-dose schedule using pembrolizumab 200 is defined as an occult or unknown primary cancer; this is an mg every three weeks was subsequently assessed in a phase 1b uncommon disease, accounting for about 5% of patients presenting to expansion cohort of 132 patients with recurrent or metastatic referral centers. Although patients with very small tonsil and tongue squamous cell H&N cancer.528 Eighty-two percent of these patients base cancers frequently present with enlarged neck nodes and are had previously received systemic therapy for their recurrent or initially classified as an unknown primary, most will eventually be metastatic disease. At 6 months, the overall survival rate was 59%, diagnosed by directed biopsy and tonsillectomy. H&N cancer of

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

unknown primary site is a highly curable disease. After appropriate PET/CT scan should only be done (before biopsy) if other tests do not evaluation and treatment, most patients experience low morbidity and reveal a primary. HPV-16 and EBV testing are suggested for squamous many will be cured. The primary tumor becomes apparent on follow-up cell or undifferentiated histology.498,529-532 HPV testing can be useful in only in a few cases. Patients and oncologists are often concerned when workup and management of cancers of the neck of unknown primary.533 the primary cancer cannot be found. This concern may lead to An HPV-positive test strongly suggests an occult primary is located in intensive, fruitless, and costly diagnostic maneuvers. the tonsil or base of tongue regions, permitting one to customize radiation targets to these mucosal regions.331 Most patients older than 40 years who present with a neck mass prove to have metastatic cancer. The source of the lymphadenopathy is When the imaging studies and a complete H&N examination do not almost always discovered in the course of a complete H&N reveal a primary tumor, then an examination under anesthesia should examination, which should be performed on all patients with neck be performed. Mucosal sites should be inspected and examined. masses before other studies are initiated. The following should be Appropriate endoscopies with directed biopsies of likely primary sites assessed during office evaluation: 1) risk factors (eg, tobacco or alcohol are recommended, but they seldom disclose a primary cancer. Many use); 2) antecedent history of malignancy; and 3) prior resection, primary cancers are identified after tonsillectomy. However, the destruction, or regression of cutaneous lesions. therapeutic benefit of this surgery is uncertain, because when patients have been treated without tonsillectomy, only a few develop a clinically Workup significant primary tumor. Patients with a neck mass should have a complete H&N examination. FNA is preferred (over open biopsy), which generally guides Treatment management and treatment planning. Unless FNA is inconclusive, core Neck dissection is recommended for all patients with or open biopsy should be avoided because it may alter or interfere with thyroglobulin-negative and calcitonin-negative adenocarcinoma (see subsequent treatment. Open biopsy should not be performed unless the Occult Primary in the NCCN Guidelines for Head and Neck Cancers). If patient is prepared for definitive surgical management of the malignancy the metastatic adenocarcinoma presents high in the neck, as indicated, if documented in the operating room. This management parotidectomy may be included with the neck dissection. After neck may entail a formal neck dissection. Therefore, an open biopsy of an dissection, management depends on the findings (ie, N1 without undiagnosed neck mass should not be undertaken lightly, and patients extracapsular spread, N2 or N3 without extracapsular spread, or should be apprised of treatment decisions and related sequelae. extracapsular spread) (see Occult Primary in the NCCN Guidelines for Head and Neck Cancers). When a needle biopsy shows squamous cell carcinoma, adenocarcinoma, or anaplastic/undifferentiated epithelial cancer and no Among NCCN Member Institutions, significant variation exists regarding primary site has been found, additional studies are needed (see Occult the management of squamous cell carcinoma, poorly differentiated or Primary in the NCCN Guidelines for Head and Neck Cancers). A FDG- nonkeratinizing squamous cell carcinoma, anaplastic cancer (not

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

thyroid) of unknown primary site, or other uncommon histologies. Most salivary gland tumors are located on the hard palate. Approximately panel members believe such patients should be managed with surgery 20% of the parotid gland tumors are malignant; the incidence of (which is preferred for N1 disease) and neck dissection (levels I–V) malignancy in submandibular and minor salivary gland tumors is followed by RT or systemic therapy/RT. The following options are also approximately 50% and 80%, respectively. These malignant tumors recommended: 1) chemoradiation for those with N2 or greater disease constitute a broad spectrum of histologic types, including (category 2B); 2) primary RT for those with N1 disease (category 2B); or mucoepidermoid, acinic, adenocarcinoma, adenoid cystic carcinoma, 3) induction chemotherapy (category 3) followed by chemoradiation or malignant myoepithelial tumors, and squamous carcinoma. The primary RT (see Occult Primary in the NCCN Guidelines for Head and Neck diagnosis of squamous carcinoma of the parotid gland is rare; however, Cancers). A neck dissection may be recommended after treatment, the parotid is a frequent site of metastasis from skin cancer.535 depending on the clinical response. Prognosis and tendency to metastasize vary among these histologic types. Major prognostic factors are histologic grade, tumor size, and After a neck dissection, recommendations vary depending on the local invasion. Staging is done using the AJCC Cancer Staging Manual amount of nodal disease and the presence or absence of extracapsular (7th edition) (see Table 5).31 spread. For N1 disease without extracapsular spread, NCCN Member Institutions recommend either: 1) radiation that encompasses the target Treatment volume; or 2) careful observation with regular H&N examinations. The major therapeutic approach for salivary gland tumors is adequate Postoperative radiation or considering concurrent chemoradiation and appropriate surgical resection.536-539 Surgical intervention requires (category 2B for chemoradiation) is recommended for N2 or N3 disease careful planning and execution, particularly in parotid tumor surgery without extracapsular spread (see Occult Primary in the NCCN because the facial nerve is in the gland, which should be preserved if Guidelines for Head and Neck Cancers). For extracapsular spread, the nerve is not directly involved by the tumor. Most parotid gland concurrent chemoradiation is a category 1 recommendation; RT alone tumors are located in the superficial lobe, and if the facial nerve is is an option (see Occult Primary in the NCCN Guidelines for Head and functioning preoperatively, the nerve can be preserved in most 100,101 Neck Cancers). Note that the Principles of Radiation Therapy were patients.540 The facial nerve should be sacrificed if there is preoperative extensively revised for this site (see Occult Primary in the NCCN facial nerve involvement with facial palsy or if there is direct invasion of Guidelines for Head and Neck Cancers; see also Head and Neck the tumor into the nerve where the tumor cannot be separated from the Radiation Therapy in this Discussion). nerve. Malignant deep lobe parotid tumors are quite rare; however, they are generally a challenge for the surgeon because the patient may Salivary Gland Tumors require superficial parotidectomy and identification and retraction of the Salivary gland tumors can arise in the major salivary glands (ie, parotid, facial nerve to remove the deep lobe parotid tumor. submandibular, sublingual) or in one of the minor salivary glands, which are widely spread throughout the aerodigestive tract.534 Many minor

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

The panel recommends photon, photon/electron, or highly conformal RT salivary gland malignant histologies.546-553 Although targeted therapy is for definitive radiation treatment. Pooled analyses of several studies associated with stable disease, it is minimally active and not showed better local control of advanced disease with neutron therapy, recommended outside of clinical trials.550,554 relative to photo therapy.541,542 However, risk of late effects with neutron therapy is high and tends to increase over time, with estimates as high Follow-up as 20% at 9 years.542,543 The panel no longer recommends neutron Recommendations for surveillance are in the algorithm (see Follow-up therapy for salivary gland cancers due to the diminishing demand and Recommendations in the NCCN Guidelines for Head and Neck closure of all but one center in the United States. Neutron therapy use Cancers). has decreased over the years due to cost and toxicity considerations, as well as a lack of widely accepted clinical applications based on the Mucosal Melanoma of the Head and Neck limited amount of randomized trial data specific to salivary gland tumors MM is a rare but highly aggressive neoplasm with a poor in concerns regarding its methodologic robustness. The panel prognosis.555,556 It mainly occurs throughout the upper aerodigestive recognizes the potential clinical value of neutron therapy for select tract.557 Most MM (70%–80%) occurs in the nasal cavity or paranasal patients. sinus region, and most of the remainder develops in the oral cavity.558 The incidence of nasal cavity MM appears to be increasing.555 Most malignant deep lobe parotid tumors will require postoperative RT Sinonasal MM is typically confined to the primary site at presentation.559 because of adverse features such as the limitations of surgical margins Oral cavity MM more frequently presents with clinically apparent lymph in the resection of these tumors (see the NCCN Guidelines for Salivary node metastasis.560 No etiologic risk factors are yet apparent. Gland Tumors).536,538,544 RT is also used in an adjuvant setting for tumors with other adverse features (eg, intermediate, high grade);537 systemic Workup and Staging therapy/RT (category 2B) can also be considered (see the NCCN Workup for MM should include clinical examination and CT and/or MRI 545 Guidelines for Salivary Gland Tumors). Efficacy data for systemic with contrast for paranasal sinus disease and appropriate imaging for therapy/RT in this setting are limited. Extensive safety data are other mucosal sites. FDG-PET/CT scanning and brain MRI may be available from the management of squamous cell H&N cancers. With considered to define distant disease in more advanced situations. The regard to unresectable salivary gland tumors, the NCCN Panel had less AJCC Cancer Staging Manual (7th edition) includes a staging system for consensus about chemoradiation (which is reflected in the category 2B MM (see Table 6).31 The AJCC staging recognizes 2 key factors specific recommendations), because there are few published trials. to MM: 1) the poor prognosis of MM even with a limited primary burden of disease; and 2) there is still some gradation of survival based on the Systemic therapy may be used for palliation in advanced disease. burden of disease as reflected in local, regional, and distant extent. Various agents alone or in combination (eg, cisplatin, Thus, the AJCC staging system for MM begins with stage III disease as cyclophosphamide, doxorubicin; epirubicin; mitoxantrone; carboplatin the most limited form of disease (similar to anaplastic thyroid and vinorelbine) have been shown in small series to be active for some

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

carcinoma), and the stages reflect the local burden of disease, as well dissection (see third paragraph in this section).568 Retrospective studies as regional and distant extent. In addition, the AJCC staging system in MM have shown local recurrence to be common after surgery reflects the fact that MM occurs at all mucosal sites in the H&N. alone.569 After using postoperative radiation, lower rates of local and Therefore, rules for classifying, staging, and surgical principles should neck recurrence have been seen in historical comparison series.564,570-573 be based on the appropriate anatomic site of origin. Reasonable local control outcomes using RT alone in unresectable or medically inoperable cases have been reported in small cohort series of Treatment MMs.574-576 Although limited data exist on treatment options, primary treatment should be surgical for stage III to IVA disease; however, surgery is not Primary size or thickness is not used as a risk factor when considering recommended for stage IVB to C disease.561 Adjuvant radiation appears RT to the primary site; all invasive primaries are considered at high risk effective in improving local control and survival in most case series.562-564 for local recurrence. For sinonasal primary sites, target volumes may Postoperative radiation is clearly indicated in more advanced cases.565 include the primary site without elective treatment of the neck (see the The role of radiation in stage III disease is not clear, but it can be NCCN Guidelines for Mucosal Melanoma). Because oral cavity primary considered on an individual basis by the treating clinicians. NCCN sites are felt to be at a higher risk for failure in the neck, elective strongly encourages clinical trials for all patients with MM to better management with neck dissection and RT may be applied (see the define treatment choices at all stages of the disease. NCCN Guidelines for Mucosal Melanoma).

Neck dissection and postoperative radiation are recommended for RT is often recommended in the postoperative management of MMs. clinical nodal disease.566,567 The role of elective neck treatment is Indications for postoperative radiation to the neck are generally unclear. The extension of elective treatment to the neck seems extrapolated from cutaneous melanoma. An Australian-New Zealand unwarranted in most cases of N0 paranasal sinus MM (see the NCCN consortium reported on a randomized trial (250 patients) of Guidelines for Mucosal Melanoma). However, for oral cavity disease, postoperative RT versus observation in patients with palpable the likelihood of positive disease is significantly higher and the adenopathy from cutaneous primaries. Postoperative RT was treatment can be better localized to the ipsilateral neck with both associated with a significant reduction in relapse in the nodal basin surgery and radiation (see the NCCN Guidelines for Mucosal (19% vs. 31%) and a significant improvement in lymph node field 568 Melanoma). Therefore, elective treatment to the neck for oral cavity MM control. Only 20 patients relapsed who received RT, whereas 34 appears justifiable. patients relapsed who received observation only (P = .04). However, no significant differences in overall survival were reported. Radiation Therapy The role of RT in MM has not been evaluated in prospective trials. Considering this trial and retrospective studies in MM, the NCCN Panel However, results of a randomized trial in cutaneous melanoma are recommends postoperative RT for the following high-risk features: considered relevant to MM in the postoperative setting after neck extracapsular disease, involvement of 2 or more neck or intraparotid

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

nodes, any node 3 cm or greater, neck dissection (alone) with no further specific mutations.583-586 Therefore, c-KIT inhibitors are reasonable to basin dissection, or recurrence in the neck or soft tissue after initial use in patients with MM who have c-KIT mutations (ie, exon 11 or 13 surgical resection.577,578 Conventional fractionation is recommended (at mutations).581,587,588 Although vemurafenib is recommended for patients 2 Gy per fraction to a total postoperative dose of 60–66 Gy). The with cutaneous melanoma who have the V600E mutation of the BRAF Australian-New Zealand randomized trial used 48 Gy in 20 fractions gene, patients with MM rarely have this mutation.581,588,589 (240 cGy/fraction) to the neck, axilla, or groin.568 However, the NCCN panel prefers conventional fractionation to somewhat higher total doses Follow-up (60–66 Gy) in the neck because of concerns about late effects from Recommendations for surveillance are provided in the algorithm (see larger dose per fraction, which may not be fully expressed for many Follow-up Recommendations in the NCCN Guidelines for Head and years after treatment. The following schedules may also be used: 1) 48 Neck Cancers). Note that physical examination for MM should include to 50 Gy (2.4–3 Gy/fraction); or 2) 30 to 36 Gy (6 Gy/fraction).568,570,578 endoscopic inspection for paranasal sinus disease.

IMRT may be very useful in helping to achieve homogenous dose Recommended Reading List distributions and to spare critical organs, especially in paranasal sinus Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation sites.190,468,579 Reports suggest that the use of hypofractionation in therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92-98. cutaneous melanomas (which is convenient) is associated with good Adelstein DJ, Ridge JA, Gillison ML, et al. Head and neck squamous cell cancer and the human outcomes but no clear advantage in cancer control. Little experience is papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9-10, 2008, Washington, D.C. Head Neck 2009;31:1393-1422. available using large dose per fraction in mucosal sites. Because of the Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with close proximity of neural structures and risk of late effects, advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol hypofractionation (if used) must be carefully planned and delivered.579 1998;16:1310-1317. Care should be taken when RT is used in combination with BRAF Ang KK, Chen A, Curran WJ Jr, et al. Head and neck carcinoma in the United States: first comprehensive report of the Longitudinal Oncology Registry of Head and Neck Carcinoma inhibitors, as concurrent use has been found to be associated with (LORHAN). Cancer 2012;118:5783-5792. grade ≥3 dermatologic reactions, and potentially lethal hemorrhaging in Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck 580 cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials the liver, lung, and brain, have all been reported. of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27:843-850. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant Systemic Therapy chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952. Systemic therapy used for cutaneous melanoma (eg, interleukin-2) is Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation recommended for MM (see Systemic Therapy for Advanced or between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21-28. Metastatic Melanoma in the NCCN Guidelines for [cutaneous] Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head Melanoma, available at www.NCCN.org).559,581 Interferon and interleukin and neck cancer: a meta-analysis. Lancet 2006;368:843-854. have been used to treat MM.581,582 Data suggest that c-KIT inhibitors (eg, Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck imatinib) may be useful in selected patients with metastatic MM and

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol Pignon JP, le Maître A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck 2012;13:145-153. cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14. Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998;338:1798-1804. Rosenthal DI, Trotti A. Strategies for managing radiation-induced mucositis in head and neck cancer. Semin Radiat Oncol 2009;19:29-34. Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2006;24:2644-2652. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-1127. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-1944. Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012;84:1198-1205. DeVita Jr VT, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology, 9th edition. Philadelphia: Lippincott Williams & Wilkins; 2011. Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 2013;31:845-852. Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48:7-16. Furniss CS, McClean MD, Smith JF, et al. Human papillomavirus 16 and head and neck squamous cell carcinoma. Int J Cancer 2007;120:2386-2392. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709-720. Kutler DI, Patel SG, Shah JP. The role of neck dissection following definitive chemoradiation. Oncology (Williston Park) 2004;18:993-998; discussion 999, 1003-1004, 1007. Laurie SA, Ho AL, Fury MG, et al. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. Lancet Oncol 2011;12:815-824. Laurie SA, Licitra L. Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol 2006;24:2673-2678. Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996;88:890-899. Piccirillo JF. Importance of comorbidity in head and neck cancer. Laryngoscope 2000;110:593-602. Pignon JP, Bourhis J, Domenge C, et al on behalf of the MACH-NC Collaborative Group. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. Lancet 2000;355:949-955.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Figure 1: Anatomic Sites and Subsites of the Head and Figure 2: Level Designation for Cervical Lymphatics in Neck the Right Neck

Reprinted with permission from CMP Healthcare Media. Source: Cancer Management: A Reprinted with permission from CMP Healthcare Media. Source: Cancer Management: A Multidisciplinary Approach, 9th ed. Pazdur R, Coia L, Hoskins W, et al (eds), Chapter 4. Multidisciplinary Approach, 9th ed. Pazdur R, Coia L, Hoskins W, et al (eds), Chapter 4. Copyright 2005, All rights reserved. Copyright 2005, All rights reserved.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

References 9. Schlecht NF, Burk RD, Adrien L, et al. Gene expression profiles in HPV-infected head and neck cancer. J Pathol 2007;213:283-293. 1. Mendenhall WM, Werning JW, Pfister DG. Treatment of head and Available at: http://www.ncbi.nlm.nih.gov/pubmed/17893858. neck cancer. In: DeVita Jr. VT, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of 10. Sturgis EM, Cinciripini PM. Trends in head and neck cancer Oncology. Philadelphia: Lippincott Williams & Wilkins; 2011. incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer 2007;110:1429- 2. DeVita Jr V, Lawrence T, Rosenberg S. DeVita, Hellman, and 1435. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17724670. Rosenberg’s Cancer: Principles & Practice of Oncology, 9th edition. Philadelphia: Lippincott Williams & Wilkins; 2011. 11. Adelstein DJ, Ridge JA, Gillison ML, et al. Head and neck squamous cell cancer and the human papillomavirus: summary of a 3. Baxi S, Fury M, Ganly I, et al. Ten years of progress in head and National Cancer Institute State of the Science Meeting, November 9-10, neck cancers. J Natl Compr Canc Netw 2012;10:806-810. Available at: 2008, Washington, D.C. Head Neck 2009;31:1393-1422. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22773796. http://www.ncbi.nlm.nih.gov/pubmed/19787782. 4. U.S. National Library of Medicine-Key MEDLINE® Indicators. 12. Agalliu I, Gapstur S, Chen Z, et al. Associations of oral alpha-, beta- Available at: http://www.nlm.nih.gov/bsd/bsd_key.html. Accessed July , and gamma-human papillomavirus types with risk of incident head and 24, 2014. neck cancer. JAMA Oncol 2016. Available at: 5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J http://www.ncbi.nlm.nih.gov/pubmed/26794505. Clin 2017;67:7-30. Available at: 13. Snow AN, Laudadio J. Human papillomavirus detection in head and https://www.ncbi.nlm.nih.gov/pubmed/28055103. neck squamous cell carcinomas. Adv Anat Pathol 2010;17:394-403. 6. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal Available at: https://www.ncbi.nlm.nih.gov/pubmed/20966645. association between human papillomavirus and a subset of head and 14. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence neck cancers. J Natl Cancer Inst 2000;92:709-720. Available at: trends for human papillomavirus-related and -unrelated oral squamous http://www.ncbi.nlm.nih.gov/pubmed/10793107. cell carcinomas in the United States. J Clin Oncol 2008;26:612-619. 7. Applebaum KM, Furniss CS, Zeka A, et al. Lack of association of Available at: http://www.ncbi.nlm.nih.gov/pubmed/18235120. alcohol and tobacco with HPV16-associated head and neck cancer. J 15. D'Souza G, Zhang HH, D'Souza WD, et al. Moderate predictive Natl Cancer Inst 2007;99:1801-1810. Available at: value of demographic and behavioral characteristics for a diagnosis of http://www.ncbi.nlm.nih.gov/pubmed/18042931. HPV16-positive and HPV16-negative head and neck cancer. Oral Oncol 8. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human 2010;46:100-104. Available at: papillomavirus and oropharyngeal cancer. N Engl J Med https://www.ncbi.nlm.nih.gov/pubmed/20036610. 2007;356:1944-1956. Available at: 16. Gillison ML, Alemany L, Snijders PJ, et al. Human papillomavirus http://www.ncbi.nlm.nih.gov/pubmed/17494927. and diseases of the upper airway: head and neck cancer and

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

77. Byers RM. Neck dissection: concepts, controversies, and technique. 85. Patel RS, Clark J, Wyten R, et al. Squamous cell carcinoma from an Semin Surg Oncol 1991;7:9-13. Available at: unknown head and neck primary site: a "selective treatment" approach. http://www.ncbi.nlm.nih.gov/pubmed/2003186. Arch Otolaryngol Head Neck Surg 2007;133:1282-1287. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18086973. 78. Stringer SP. Current concepts in surgical management of neck metastases from head and neck cancer. Oncology (Williston Park) 86. Sivanandan R, Kaplan MJ, Lee KJ, et al. Long-term results of 100 1995;9:547-554. Available at: consecutive comprehensive neck dissections: implications for selective http://www.ncbi.nlm.nih.gov/pubmed/8719100. neck dissections. Arch Otolaryngol Head Neck Surg 2004;130:1369- 1373. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15611394. 79. Robbins KT, Clayman G, Levine PA, et al. Neck dissection classification update: revisions proposed by the American Head and 87. Liauw SL, Mancuso AA, Amdur RJ, et al. Postradiotherapy neck Neck Society and the American Academy of Otolaryngology-Head and dissection for lymph node-positive head and neck cancer: the use of Neck Surgery. Arch Otolaryngol Head Neck Surg 2002;128:751-758. computed tomography to manage the neck. J Clin Oncol 2006;24:1421- Available at: http://www.ncbi.nlm.nih.gov/pubmed/12117328. 1427. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16549836.

80. Candela FC, Kothari K, Shah JP. Patterns of cervical node 88. Porceddu SV, Jarmolowski E, Hicks RJ, et al. Utility of positron metastases from squamous carcinoma of the oropharynx and emission tomography for the detection of disease in residual neck hypopharynx. Head Neck 1990;12:197-203. Available at: nodes after (chemo)radiotherapy in head and neck cancer. Head Neck http://www.ncbi.nlm.nih.gov/pubmed/2358329. 2005;27:175-181. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15627258. 81. Candela FC, Shah J, Jaques DP, Shah JP. Patterns of cervical node metastases from squamous carcinoma of the larynx. Arch 89. Yao M, Smith RB, Hoffman HT, et al. Clinical significance of Otolaryngol Head Neck Surg 1990;116:432-435. Available at: postradiotherapy [18F]-fluorodeoxyglucose positron emission http://www.ncbi.nlm.nih.gov/pubmed/2317325. tomography imaging in management of head-and-neck cancer-a long- term outcome report. Int J Radiat Oncol Biol Phys 2009;74:9-14. 82. Shah JP, Candela FC, Poddar AK. The patterns of cervical lymph Available at: http://www.ncbi.nlm.nih.gov/pubmed/18930358. node metastases from squamous carcinoma of the oral cavity. Cancer 1990;66:109-113. Available at: 90. Lango MN, Myers JN, Garden AS. Controversies in surgical http://www.ncbi.nlm.nih.gov/pubmed/2354399. management of the node-positive neck after chemoradiation. Semin Radiat Oncol 2009;19:24-28. Available at: 83. Ferlito A, Rinaldo A, Silver CE, et al. Elective and therapeutic http://www.ncbi.nlm.nih.gov/pubmed/19028342. selective neck dissection. Oral Oncol 2006;42:14-25. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15979381. 91. Isles MG, McConkey C, Mehanna HM. A systematic review and meta-analysis of the role of positron emission tomography in the follow 84. Schmitz S, Machiels JP, Weynand B, et al. Results of selective neck up of head and neck squamous cell carcinoma following radiotherapy or dissection in the primary management of head and neck squamous cell chemoradiotherapy. Clin Otolaryngol 2008;33:210-222. Available at: carcinoma. Eur Arch Otorhinolaryngol 2009;266:437-443. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18559026. http://www.ncbi.nlm.nih.gov/pubmed/18648835.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

92. Sheikhbahaei S, Taghipour M, Ahmad R, et al. Diagnostic accuracy after definitive radiotherapy with or without systemic therapy. Head of follow-up FDG PET or PET/CT in patients with head and neck cancer Neck 2011;33:1675-1682. Available at: after definitive treatment: a systematic review and meta-analysis. AJR http://www.ncbi.nlm.nih.gov/pubmed/22076976. Am J Roentgenol 2015;205:629-639. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26295652. 99. Mehanna H, Wong WL, McConkey CC, et al. PET-CT surveillance versus neck dissection in advanced head and neck cancer. N Engl J 93. Corry J, Peters L, Fisher R, et al. N2-N3 neck nodal control without Med 2016;374:1444-1454. Available at: planned neck dissection for clinical/radiologic complete responders- https://www.ncbi.nlm.nih.gov/pubmed/27007578. results of Trans Tasman Radiation Oncology Group Study 98.02. Head Neck 2008;30:737-742. Available at: 100. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation http://www.ncbi.nlm.nih.gov/pubmed/18286488. with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952. Available at: 94. Lau H, Phan T, Mackinnon J, Matthews TW. Absence of planned http://www.ncbi.nlm.nih.gov/pubmed/15128894. neck dissection for the N2-N3 neck after chemoradiation for locally advanced squamous cell carcinoma of the head and neck. Arch 101. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative Otolaryngol Head Neck Surg 2008;134:257-261. Available at: concurrent radiotherapy and chemotherapy for high-risk squamous-cell http://www.ncbi.nlm.nih.gov/pubmed/18347249. carcinoma of the head and neck. N Engl J Med 2004;350:1937-1944. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15128893. 95. Ong SC, Schoder H, Lee NY, et al. Clinical utility of 18F-FDG PET/CT in assessing the neck after concurrent chemoradiotherapy for 102. Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the Locoregional advanced head and neck cancer. J Nucl Med RTOG 9501/intergroup phase III trial: postoperative concurrent radiation 2008;49:532-540. Available at: therapy and chemotherapy in high-risk squamous cell carcinoma of the http://www.ncbi.nlm.nih.gov/pubmed/18344440. head and neck. Int J Radiat Oncol Biol Phys 2012;84:1198-1205. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22749632. 96. Nayak JV, Walvekar RR, Andrade RS, et al. Deferring planned neck dissection following chemoradiation for stage IV head and neck cancer: 103. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally the utility of PET-CT. Laryngoscope 2007;117:2129-2134. Available at: advanced head and neck cancers: a comparative analysis of concurrent http://www.ncbi.nlm.nih.gov/pubmed/17921898. postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27:843-850. Available 97. Abgral R, Querellou S, Potard G, et al. Does 18F-FDG PET/CT at: http://www.ncbi.nlm.nih.gov/pubmed/16161069. improve the detection of posttreatment recurrence of head and neck squamous cell carcinoma in patients negative for disease on clinical 104. Bachaud JM, Cohen-Jonathan E, Alzieu C, et al. Combined follow-up? J Nucl Med 2009;50:24-29. Available at: postoperative radiotherapy and weekly cisplatin infusion for locally http://www.ncbi.nlm.nih.gov/pubmed/19091901. advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys 1996;36:999-1004. Available at: 98. Porceddu SV, Pryor DI, Burmeister E, et al. Results of a prospective http://www.ncbi.nlm.nih.gov/pubmed/8985019. study of positron emission tomography-directed management of residual nodal abnormalities in node-positive head and neck cancer

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

105. Shah JP, Cendon RA, Farr HW, Strong EW. Carcinoma of the oral carcinoma (RTOG 0615): a phase 2 multi-institutional trial. Lancet cavity. factors affecting treatment failure at the primary site and neck. Oncol 2012;13:172-180. Available at: Am J Surg 1976;132:504-507. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22178121. http://www.ncbi.nlm.nih.gov/pubmed/1015542. 113. Paris KJ, Spanos WJ, Jr., Lindberg RD, et al. Phase I-II study of 106. Looser KG, Shah JP, Strong EW. The significance of "positive" multiple daily fractions for palliation of advanced head and neck margins in surgically resected epidermoid carcinomas. Head Neck Surg malignancies. Int J Radiat Oncol Biol Phys 1993;25:657-660. Available 1978;1:107-111. Available at: at: http://www.ncbi.nlm.nih.gov/pubmed/7681051. http://www.ncbi.nlm.nih.gov/pubmed/755803. 114. Stevens CM, Huang SH, Fung S, et al. Retrospective study of 107. Johnson JT, Barnes EL, Myers EN, et al. The extracapsular spread palliative radiotherapy in newly diagnosed head and neck carcinoma. Int of tumors in cervical node metastasis. Arch Otolaryngol 1981;107:725- J Radiat Oncol Biol Phys 2011;81:958-963. Available at: 729. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7316852. http://www.ncbi.nlm.nih.gov/pubmed/20950952.

108. Feldman M, Fletcher GH. Analysis of the parameters relating to 115. Porceddu SV, Rosser B, Burmeister BH, et al. Hypofractionated failures above the clavicles in patients treated by postoperative radiotherapy for the palliation of advanced head and neck cancer in irradiation for squamous cell carcinomas of the oral cavity or patients unsuitable for curative treatment--"Hypo Trial". Radiother Oncol oropharynx. Int J Radiat Oncol Biol Phys 1982;8:27-30. Available at: 2007;85:456-462. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7061253. http://www.ncbi.nlm.nih.gov/pubmed/18036689.

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110. Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for 117. Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology postoperative radiation therapy of head and neck cancer: first report of Group (RTOG) phase III randomized study to compare a prospective randomized trial. Int J Radiat Oncol Biol Phys 1993;26:3- hyperfractionation and two variants of accelerated fractionation to 11. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8482629. standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 111. Harari PM, Harris J, Kies MS, et al. Postoperative 2000;48:7-16. Available at: chemoradiotherapy and cetuximab for high-risk squamous cell http://www.ncbi.nlm.nih.gov/pubmed/10924966. carcinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. J Clin Oncol 2014;32:2486-2495. Available at: 118. Beitler JJ, Zhang Q, Fu KK, et al. Final results of local-regional https://www.ncbi.nlm.nih.gov/pubmed/25002723. control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J 112. Lee NY, Zhang Q, Pfister DG, et al. Addition of bevacizumab to Radiat Oncol Biol Phys 2014;89:13-20. Available at: standard chemoradiation for locoregionally advanced nasopharyngeal http://www.ncbi.nlm.nih.gov/pubmed/24613816.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

119. Overgaard J, Hansen HS, Specht L, et al. Five compared with six 127. Garden AS, Dong L, Morrison WH, et al. Patterns of disease fractions per week of conventional radiotherapy of squamous-cell recurrence following treatment of oropharyngeal cancer with intensity carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled modulated radiation therapy. Int J Radiat Oncol Biol Phys 2013;85:941- trial. Lancet 2003;362:933-940. Available at: 947. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22975604. http://www.ncbi.nlm.nih.gov/pubmed/14511925. 128. Daly ME, Le QT, Maxim PG, et al. Intensity-modulated 120. Fletcher GH. Textbook of Radiotherapy (ed 3rd): Lea & Febiger; radiotherapy in the treatment of oropharyngeal cancer: clinical 1980:194-219. outcomes and patterns of failure. Int J Radiat Oncol Biol Phys 2010;76:1339-1346. Available at: 121. Northrop M, Fletcher GH, Jesse RH, Lindberg RD. Evolution of http://www.ncbi.nlm.nih.gov/pubmed/19540068. neck disease in patients with primary squamous cell carcinoma of the oral tongue, floor of mouth, and palatine arch, and clinically positive 129. Thames HD, Jr., Withers HR, Peters LJ, Fletcher GH. Changes in neck nodes neither fixed nor bilateral. Cancer 1972;29:23-30. Available early and late radiation responses with altered dose fractionation: at: http://www.ncbi.nlm.nih.gov/pubmed/5007385. implications for dose-survival relationships. Int J Radiat Oncol Biol Phys 1982;8:219-226. Available at: 122. Barkley HT, Fletcher GH. The significance of residual disease after http://www.ncbi.nlm.nih.gov/pubmed/7085377. external irradiation of squamous-cell carcinoma of the oropharynx. Radiology 1977;124:493-495. Available at: 130. Withers H, Thames H, Peters L. Differences in the fractionation http://www.ncbi.nlm.nih.gov/pubmed/877290. response of acutely and late-responding tissues In: Kaercher K, Kogelnik H, Reinartz G, eds, eds. Progress in Radio-Oncology II. Vol. 123. Arcangeli G, Friedman M, Paoluzi R. A quantitative study of late 11. New York: Raven Press; 1982:287-296. radiation effect on normal skin and subcutaneous tissues in human beings. Br J Radiol 1974;47:44-50. Available at: 131. Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated http://www.ncbi.nlm.nih.gov/pubmed/4809425. tumor clonogen repopulation during radiotherapy. Acta Oncol 1988;27:131-146. Available at: 124. Andrews JR. Dose-time relationships in cancer radiotherapy. A http://www.ncbi.nlm.nih.gov/pubmed/3390344. clinical radiobiology study of extremes of dose and time. Am J Roentgenol Radium Ther Nucl Med 1965;93:56-74. Available at: 132. Harwood AR, Beale FA, Cummings BJ, et al. T4NOMO glottic http://www.ncbi.nlm.nih.gov/pubmed/14243019. cancer: an analysis of dose-time volume factors. Int J Radiat Oncol Biol Phys 1981;7:1507-1512. Available at: 125. ICRU Report 62. Prescribing, Recording and Reporting Photon http://www.ncbi.nlm.nih.gov/pubmed/7333899. Beam Therapy (Supplement to ICRU Report 50). Journal of the ICRU 1999. Available at: 133. Amornmarn R, Prempree T, Viravathana T, et al. A therapeutic approach to early vocal cord carcinoma. Acta Radiol Oncol 126. ICRU Report 83: Prescribing, Recording, and Reporting Intensity 1985;24:321-325. Available at: Modulated Photon Beam Therapy (IMRT). Journal of the ICRU 2010;10. http://www.ncbi.nlm.nih.gov/pubmed/2994388. Available at: http://jicru.oxfordjournals.org/content/10/1.toc.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

134. Schwaibold F, Scariato A, Nunno M, et al. The effect of fraction 141. Horiot JC, Bontemps P, van den Bogaert W, et al. Accelerated size on control of early glottic cancer. Int J Radiat Oncol Biol Phys fractionation (AF) compared to conventional fractionation (CF) improves 1988;14:451-454. Available at: loco-regional control in the radiotherapy of advanced head and neck http://www.ncbi.nlm.nih.gov/pubmed/3343152. cancers: results of the EORTC 22851 randomized trial. Radiother Oncol 1997;44:111-121. Available at: 135. Kim RY, Marks ME, Salter MM. Early-stage glottic cancer: http://www.ncbi.nlm.nih.gov/pubmed/9288839. importance of dose fractionation in radiation therapy. Radiology 1992;182:273-275. Available at: 142. Konski AA, Winter K, Cole BF, et al. Quality-adjusted survival http://www.ncbi.nlm.nih.gov/pubmed/1727295. analysis of Radiation Therapy Oncology Group (RTOG) 90-03: phase III randomized study comparing altered fractionation to standard 136. Parson J. Time-dose-volume relationships in radiation therapy. In: fractionation radiotherapy for locally advanced head and neck Million R, Cassisi N, eds. Management of Head and Neck Cancer: A squamous cell carcinoma. Head Neck 2009;31:207-212. Available at: Multidisciplinary Approach, 2nd ed. Philadelphia: Lippincott Williams & http://www.ncbi.nlm.nih.gov/pubmed/19107946. Wilkins; 1994:203-243. 143. Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or 137. Yamazaki H, Nishiyama K, Tanaka E, et al. Radiotherapy for early accelerated radiotherapy in head and neck cancer: a meta-analysis. glottic carcinoma (T1N0M0): results of prospective randomized study of Lancet 2006;368:843-854. Available at: radiation fraction size and overall treatment time. Int J Radiat Oncol Biol http://www.ncbi.nlm.nih.gov/pubmed/16950362. Phys 2006;64:77-82. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16169681. 144. Baujat B, Bourhis J, Blanchard P, et al. Hyperfractionated or accelerated radiotherapy for head and neck cancer. Cochrane 138. Yu E, Shenouda G, Beaudet MP, Black MJ. Impact of radiation Database Syst Rev 2010;12:CD002026. Available at: therapy fraction size on local control of early glottic carcinoma. Int J http://www.ncbi.nlm.nih.gov/pubmed/21154350. Radiat Oncol Biol Phys 1997;37:587-591. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9112457. 145. Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant 139. Horiot JC, Le Fur R, N'Guyen T, et al. Hyperfractionation versus chemotherapy in locally advanced head and neck carcinoma (GORTEC conventional fractionation in oropharyngeal carcinoma: final analysis of 99-02): an open-label phase 3 randomised trial. Lancet Oncol a randomized trial of the EORTC cooperative group of radiotherapy. 2012;13:145-153. Available at: Radiother Oncol 1992;25:231-241. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22261362. http://www.ncbi.nlm.nih.gov/pubmed/1480768. 146. Haigentz M, Jr., Corry J, Strojan P, Ferlito A. Easing acceleration 140. Horiot JC. [Controlled clinical trials of hyperfractionated and of head and neck chemoradiotherapy. Lancet Oncol 2012;13:113-115. accelerated radiotherapy in otorhinolaryngologic cancers]. Bull Acad Available at: http://www.ncbi.nlm.nih.gov/pubmed/22261361. Natl Med 1998;182:1247-1260; discussion 1261. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9812410. 147. Budach V, Stuschke M, Budach W, et al. Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

radiation therapy alone in locally advanced head and neck cancer: final 153. Ang K, Zhang Q, Wheeler RH, et al. A phase III trial (RTOG 0129) results of the radiotherapy cooperative clinical trials group of the of two radiation-cisplatin regimens for head and neck carcinomas German Cancer Society 95-06 Prospective Randomized Trial. J Clin (HNC): Impact of radiation and cisplatin intensity on outcome [abstract]. Oncol 2005;23:1125-1135. Available at: J Clin Oncol 2010;28(Suppl 15):Abstract 5507. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15718308. http://meeting.ascopubs.org/cgi/content/abstract/28/15_suppl/5507.

148. Budach W, Hehr T, Budach V, et al. A meta-analysis of 154. Nguyen-Tan PF, Zhang Q, Ang KK, et al. Randomized phase III hyperfractionated and accelerated radiotherapy and combined trial to test accelerated versus standard fractionation in combination chemotherapy and radiotherapy regimens in unresected locally with concurrent cisplatin for head and neck carcinomas in the Radiation advanced squamous cell carcinoma of the head and neck. BMC Cancer Therapy Oncology Group 0129 trial: long-term report of efficacy and 2006;6:28. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16448551. toxicity. J Clin Oncol 2014;32:3858-3866. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25366680. 149. Bensadoun R-J, Benezery K, Dassonville O, et al. French multicenter phase III randomized study testing concurrent twice-a-day 155. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in French Head and Neck Oncology and Radiotherapy Group randomized unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC- trial comparing radiotherapy alone with concomitant radiochemotherapy GORTEC). Int J Radiat Oncol Biol Phys 2006;64:983-994. Available at: in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22:69-76. http://www.ncbi.nlm.nih.gov/pubmed/16376489. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14657228.

150. Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated 156. Denis F, Garaud P, Bardet E, et al. Late toxicity results of the irradiation with or without concurrent chemotherapy for locally advanced GORTEC 94-01 randomized trial comparing radiotherapy with head and neck cancer. N Engl J Med 1998;338:1798-1804. Available concomitant radiochemotherapy for advanced-stage oropharynx at: http://www.ncbi.nlm.nih.gov/pubmed/9632446. carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol Phys 2003;55:93-98. Available 151. Jeremic B, Shibamoto Y, Milicic B, et al. Hyperfractionated at: http://www.ncbi.nlm.nih.gov/pubmed/12504040. radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a 157. Bourhis J, Calais G, Lapeyre M, et al. Concomitant prospective randomized trial. J Clin Oncol 2000;18:1458-1464. radiochemotherapy or accelerated radiotherapy: analysis of two Available at: http://www.ncbi.nlm.nih.gov/pubmed/10735893. randomized trials of the French Head and Neck Cancer Group (GORTEC). Semin Oncol 2004;31:822-826. Available at: 152. Budach V, Stromberger C, Poettgen C, et al. Hyperfractionated http://www.ncbi.nlm.nih.gov/pubmed/15599861. accelerated radiation therapy (HART) of 70.6 Gy with concurrent 5- FU/Mitomycin C is superior to HART of 77.6 Gy alone in locally 158. Machtay M, Moughan J, Trotti A, et al. Factors associated with advanced head and neck cancer: long-term results of the ARO 95-06 severe late toxicity after concurrent chemoradiation for locally advanced randomized phase III trial. Int J Radiat Oncol Biol Phys 2015;91:916- head and neck cancer: an RTOG analysis. J Clin Oncol 2008;26:3582- 924. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25670541. 3589. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18559875.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

159. Hartford AC, Palisca MG, Eichler TJ, et al. American Society for 166. Kam MKM, Leung S-F, Zee B, et al. Prospective randomized study Therapeutic Radiology and Oncology (ASTRO) and American College of intensity-modulated radiotherapy on salivary gland function in early- of Radiology (ACR) Practice Guidelines for Intensity-Modulated stage nasopharyngeal carcinoma patients. J Clin Oncol 2007;25:4873- Radiation Therapy (IMRT). Int J Radiat Oncol Biol Phys 2009;73:9-14. 4879. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17971582. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19100920. 167. Baxi SS, Sher DJ, Pfister DG. Value considerations in the 160. Holmes T, Das R, Low D, et al. American Society of Radiation treatment of head and neck cancer: radiation, chemotherapy, and Oncology recommendations for documenting intensity-modulated supportive care. Am Soc Clin Oncol Educ Book 2014:e296-303. radiation therapy treatments. Int J Radiat Oncol Biol Phys Available at: http://www.ncbi.nlm.nih.gov/pubmed/24857116. 2009;74:1311-1318. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19616738. 168. Gregoire V, Mackie TR. State of the art on dose prescription, reporting and recording in Intensity-Modulated Radiation Therapy (ICRU 161. Nutting CM, Morden JP, Harrington KJ, et al. Parotid-sparing report No. 83). Cancer Radiother 2011;15:555-559. Available at: intensity modulated versus conventional radiotherapy in head and neck http://www.ncbi.nlm.nih.gov/pubmed/21802333. cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol 2011;12:127-136. Available at: 169. Wu Q, Manning M, Schmidt-Ullrich R, Mohan R. The potential for http://www.ncbi.nlm.nih.gov/pubmed/21236730. sparing of parotids and escalation of biologically effective dose with intensity-modulated radiation treatments of head and neck cancers: a 162. Tribius S, Bergelt C. Intensity-modulated radiotherapy versus treatment design study. Int J Radiat Oncol Biol Phys 2000;46:195-205. conventional and 3D conformal radiotherapy in patients with head and Available at: http://www.ncbi.nlm.nih.gov/pubmed/10656393. neck cancer: is there a worthwhile quality of life gain? Cancer Treat Rev 2011;37:511-519. Available at: 170. Chao KS, Majhail N, Huang CJ, et al. Intensity-modulated radiation http://www.ncbi.nlm.nih.gov/pubmed/21324605. therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: a comparison with 163. Ratko TA, Douglas GW, de Souza JA, et al. Radiotherapy conventional techniques. Radiother Oncol 2001;61:275-280. Available Treatments for Head and Neck Cancer Update. Rockville (MD); 2014. at: http://www.ncbi.nlm.nih.gov/pubmed/11730997.

164. Hunter KU, Schipper M, Feng FY, et al. Toxicities affecting quality 171. Dogan N, King S, Emami B, et al. Assessment of different IMRT of life after chemo-IMRT of oropharyngeal cancer: prospective study of boost delivery methods on target coverage and normal-tissue sparing. patient-reported, observer-rated, and objective outcomes. Int J Radiat Int J Radiat Oncol Biol Phys 2003;57:1480-1491. Available at: Oncol Biol Phys 2013;85:935-940. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14630288. http://www.ncbi.nlm.nih.gov/pubmed/23040224. 172. Li Y, Taylor JMG, Ten Haken RK, Eisbruch A. The impact of dose 165. Lohia S, Rajapurkar M, Nguyen SA, et al. A comparison of on parotid salivary recovery in head and neck cancer patients treated outcomes using intensity-modulated radiation therapy and 3- with radiation therapy. Int J Radiat Oncol Biol Phys 2007;67:660-669. dimensional conformal radiation therapy in treatment of oropharyngeal Available at: http://www.ncbi.nlm.nih.gov/pubmed/17141973. cancer. JAMA Otolaryngol Head Neck Surg 2014;140:331-337. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24557509.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

173. Vergeer MR, Doornaert PA, Rietveld DH, et al. Intensity-modulated 180. Lauve A, Morris M, Schmidt-Ullrich R, et al. Simultaneous radiotherapy reduces radiation-induced morbidity and improves health- integrated boost intensity-modulated radiotherapy for locally advanced related quality of life: results of a nonrandomized prospective study head-and-neck squamous cell carcinomas: II--clinical results. Int J using a standardized follow-up program. Int J Radiat Oncol Biol Phys Radiat Oncol Biol Phys 2004;60:374-387. Available at: 2009;74:1-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15380569. http://www.ncbi.nlm.nih.gov/pubmed/19111400. 181. Schoenfeld GO, Amdur RJ, Morris CG, et al. Patterns of failure 174. Pow EHN, Kwong DLW, McMillan AS, et al. Xerostomia and and toxicity after intensity-modulated radiotherapy for head and neck quality of life after intensity-modulated radiotherapy vs. conventional cancer. Int J Radiat Oncol Biol Phys 2008;71:377-385. Available at: radiotherapy for early-stage nasopharyngeal carcinoma: initial report on http://www.ncbi.nlm.nih.gov/pubmed/18164838. a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006;66:981-991. Available at: 182. Ang KK, Chen A, Curran WJ, Jr., et al. Head and neck carcinoma http://www.ncbi.nlm.nih.gov/pubmed/17145528. in the United States: first comprehensive report of the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN). Cancer 175. Pfister D, Cassileth B, Deng G, et al. Acupuncture for pain and 2012;118:5783-5792. Available at: dysfunction after neck dissection: Results of a randomized controlled http://www.ncbi.nlm.nih.gov/pubmed/22569917. trial. J Clin Oncol 2010;28:2565-2570. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20406930. 183. Guadagnolo BA, Liu CC, Cormier JN, Du XL. Evaluation of trends in the use of intensity-modulated radiotherapy for head and neck cancer 176. Scarantino C, LeVeque F, Swann RS, et al. Effect of pilocarpine from 2000 through 2005: socioeconomic disparity and geographic during radiation therapy: results of RTOG 97-09, a phase III randomized variation in a large population-based cohort. Cancer 2010;116:3505- study in head and neck cancer patients. J Support Oncol 2006;4:252- 3512. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20564123. 258. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16724649. 184. Chi A, Nguyen NP, Tse W, et al. Intensity modulated radiotherapy 177. Petrone D, Condemi JJ, Fife R, et al. A double-blind, randomized, for sinonasal malignancies with a focus on optic pathway preservation. placebo-controlled study of cevimeline in Sjogren's syndrome patients J Hematol Oncol 2013;6:4. Available at: with xerostomia and keratoconjunctivitis sicca. Arthritis Rheum http://www.ncbi.nlm.nih.gov/pubmed/23294673. 2002;46:748-754. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11920411. 185. Lee NY, de Arruda FF, Puri DR, et al. A comparison of intensity- modulated radiation therapy and concomitant boost radiotherapy in the 178. Gregoire V, Jeraj R, Lee JA, O'Sullivan B. Radiotherapy for head setting of concurrent chemotherapy for locally advanced oropharyngeal and neck tumours in 2012 and beyond: conformal, tailored, and carcinoma. Int J Radiat Oncol Biol Phys 2006;66:966-974. Available at: adaptive? Lancet Oncol 2012;13:e292-300. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17145527. http://www.ncbi.nlm.nih.gov/pubmed/22748268. 186. de Arruda FF, Puri DR, Zhung J, et al. Intensity-modulated 179. Galvin JM, De Neve W. Intensity modulating and other radiation radiation therapy for the treatment of oropharyngeal carcinoma: the therapy devices for dose painting. J Clin Oncol 2007;25:924-930. Memorial Sloan-Kettering Cancer Center experience. Int J Radiat Oncol Available at: http://www.ncbi.nlm.nih.gov/pubmed/17350940.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Biol Phys 2006;64:363-373. Available at: 194. Turaka A, Li T, Sharma NK, et al. Increased recurrences using http://www.ncbi.nlm.nih.gov/pubmed/15925451. intensity-modulated radiation therapy in the postoperative setting. Am J Clin Oncol 2010;33:599-603. Available at: 187. Garden AS, Morrison WH, Wong P-F, et al. Disease-control rates http://www.ncbi.nlm.nih.gov/pubmed/21063195. following intensity-modulated radiation therapy for small primary oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;67:438- 195. Chen AM, Farwell DG, Luu Q, et al. Marginal misses after 444. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17141972. postoperative intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2011;80:1423-1429. Available at: 188. Eisbruch A, Levendag PC, Feng FY, et al. Can IMRT or http://www.ncbi.nlm.nih.gov/pubmed/20656416. brachytherapy reduce dysphagia associated with chemoradiotherapy of head and neck cancer? The Michigan and Rotterdam experiences. Int J 196. Eisbruch A, Marsh LH, Dawson LA, et al. Recurrences near base Radiat Oncol Biol Phys 2007;69:S40-42. Available at: of skull after IMRT for head-and-neck cancer: implications for target http://www.ncbi.nlm.nih.gov/pubmed/17848291. delineation in high neck and for parotid gland sparing. Int J Radiat Oncol Biol Phys 2004;59:28-42. Available at: 189. Wolden SL, Chen WC, Pfister DG, et al. Intensity-modulated http://www.ncbi.nlm.nih.gov/pubmed/15093896. radiation therapy (IMRT) for nasopharynx cancer: update of the Memorial Sloan-Kettering experience. Int J Radiat Oncol Biol Phys 197. Rosenthal DI, Trotti A. Strategies for managing radiation-induced 2006;64:57-62. Available at: mucositis in head and neck cancer. Semin Radiat Oncol 2009;19:29-34. http://www.ncbi.nlm.nih.gov/pubmed/15936155. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19028343.

190. Madani I, Bonte K, Vakaet L, et al. Intensity-modulated 198. Yao M, Lu M, Savvides PS, et al. Distant metastases in head-and- radiotherapy for sinonasal tumors: Ghent University Hospital update. Int neck squamous cell carcinoma treated with intensity-modulated J Radiat Oncol Biol Phys 2009;73:424-432. Available at: radiotherapy. Int J Radiat Oncol Biol Phys 2012;83:684-689. Available http://www.ncbi.nlm.nih.gov/pubmed/18755554. at: http://www.ncbi.nlm.nih.gov/pubmed/22169673.

191. Eisbruch A. Reducing xerostomia by IMRT: what may, and may 199. Frank SJ, Rosenthal DI, Petsuksiri J, et al. Intensity-modulated not, be achieved. J Clin Oncol 2007;25:4863-4864. Available at: radiotherapy for cervical node squamous cell carcinoma metastases http://www.ncbi.nlm.nih.gov/pubmed/17971579. from unknown head-and-neck primary site: M. D. Anderson Cancer Center outcomes and patterns of failure. Int J Radiat Oncol Biol Phys 192. Hodge CW, Bentzen SM, Wong G, et al. Are we influencing 2010;78:1005-1010. Available at: outcome in oropharynx cancer with intensity-modulated radiotherapy? http://www.ncbi.nlm.nih.gov/pubmed/20207504. An inter-era comparison. Int J Radiat Oncol Biol Phys 2007;69:1032- 1041. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17967300. 200. Traynor AM, Richards GM, Hartig GK, et al. Comprehensive IMRT plus weekly cisplatin for advanced head and neck cancer: the University 193. Veldeman L, Madani I, Hulstaert F, et al. Evidence behind use of of Wisconsin experience. Head Neck 2010;32:599-606. Available at: intensity-modulated radiotherapy: a systematic review of comparative http://www.ncbi.nlm.nih.gov/pubmed/19757422. clinical studies. Lancet Oncol 2008;9:367-375. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18374290.

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201. Sher DJ, Thotakura V, Balboni TA, et al. Treatment of oral cavity 208. Kocak-Uzel E, Gunn GB, Colen RR, et al. Beam path toxicity in squamous cell carcinoma with adjuvant or definitive intensity-modulated candidate organs-at-risk: assessment of radiation emetogenesis for radiation therapy. Int J Radiat Oncol Biol Phys 2011;81:e215-222. patients receiving head and neck intensity modulated radiotherapy. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21531515. Radiother Oncol 2014;111:281-288. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24746582. 202. Geretschlager A, Bojaxhiu B, Crowe S, et al. Outcome and patterns of failure after postoperative intensity modulated radiotherapy 209. Eisbruch A, Schwartz M, Rasch C, et al. Dysphagia and aspiration for locally advanced or high-risk oral cavity squamous cell carcinoma. after chemoradiotherapy for head-and-neck cancer: which anatomic Radiat Oncol 2012;7:175. Available at: structures are affected and can they be spared by IMRT? Int J Radiat http://www.ncbi.nlm.nih.gov/pubmed/23088283. Oncol Biol Phys 2004;60:1425-1439. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15590174. 203. Schoenfeld JD, Sher DJ, Norris CM, Jr., et al. Salivary gland tumors treated with adjuvant intensity-modulated radiotherapy with or 210. Brown PD, Foote RL, McLaughlin MP, et al. A historical without concurrent chemotherapy. Int J Radiat Oncol Biol Phys prospective cohort study of carotid artery stenosis after radiotherapy for 2012;82:308-314. Available at: head and neck malignancies. Int J Radiat Oncol Biol Phys http://www.ncbi.nlm.nih.gov/pubmed/21075557. 2005;63:1361-1367. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16169673. 204. Gomez DR, Zhung JE, Gomez J, et al. Intensity-modulated radiotherapy in postoperative treatment of oral cavity cancers. Int J 211. Citrin D, Mansueti J, Likhacheva A, et al. Long-term outcomes and Radiat Oncol Biol Phys 2009;73:1096-1103. Available at: toxicity of concurrent paclitaxel and radiotherapy for locally advanced http://www.ncbi.nlm.nih.gov/pubmed/18707827. head-and-neck cancer. Int J Radiat Oncol Biol Phys 2009;74:1040- 1046. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19117692. 205. Lee NY, O'Meara W, Chan K, et al. Concurrent chemotherapy and intensity-modulated radiotherapy for locoregionally advanced laryngeal 212. Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of and hypopharyngeal cancers. Int J Radiat Oncol Biol Phys RTOG 91-11: a comparison of three nonsurgical treatment strategies to 2007;69:459-468. Available at: preserve the larynx in patients with locally advanced larynx cancer. J http://www.ncbi.nlm.nih.gov/pubmed/17493769. Clin Oncol 2013;31:845-852. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23182993. 206. Beadle BM, Liao KP, Giordano SH, et al. Reduced feeding tube duration with intensity-modulated radiation therapy for head and neck 213. Awan MJ, Mohamed AS, Lewin JS, et al. Late radiation-associated cancer: a Surveillance, Epidemiology, and End Results-Medicare dysphagia (late-RAD) with lower cranial neuropathy after oropharyngeal analysis. Cancer 2017;123:283-293. Available at: radiotherapy: a preliminary dosimetric comparison. Oral Oncol https://www.ncbi.nlm.nih.gov/pubmed/27662641. 2014;50:746-752. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24906528. 207. Rosenthal DI, Chambers MS, Fuller CD, et al. Beam path toxicities to non-target structures during intensity-modulated radiation therapy for 214. Sharma J, Dougherty AH. Recurrent syncope in a cancer patient: a head and neck cancer. Int J Radiat Oncol Biol Phys 2008;72:747-755. case report and review of the literature. Cardiol Res Pract Available at: http://www.ncbi.nlm.nih.gov/pubmed/18455324.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

2011;2011:678237. Available at: 222. Demizu Y, Fujii O, Terashima K, et al. Particle therapy for mucosal http://www.ncbi.nlm.nih.gov/pubmed/21559220. melanoma of the head and neck. A single-institution retrospective comparison of proton and carbon ion therapy. Strahlenther Onkol 215. Pigneux J, Richaud PM, Lagarde C. The place of interstitial 2014;190:186-191. Available at: therapy using 192 iridium in the management of carcinoma of the lip. http://www.ncbi.nlm.nih.gov/pubmed/24362502. Cancer 1979;43:1073-1077. Available at: http://www.ncbi.nlm.nih.gov/pubmed/427714. 223. Fuji H, Yoshikawa S, Kasami M, et al. High-dose proton beam therapy for sinonasal mucosal malignant melanoma. Radiat Oncol 216. Hutcheson K, Lewin J, Garden A, et al. Early experience with IMPT 2014;9:162. Available at: for the treatment of oropharyngeal tumors: Acute toxicities and http://www.ncbi.nlm.nih.gov/pubmed/25056641. swallowing-related outcomes. Int J Radiat Oncol Biol Phys 2013;87:S604. Available at: http://www.redjournal.org/article/S0360- 224. Allen AM, Pawlicki T, Dong L, et al. An evidence based review of 3016(13)02267-0/abstract. proton beam therapy: the report of ASTRO's emerging technology committee. Radiother Oncol 2012;103:8-11. Available at: 217. Holliday EB, Frank SJ. Proton radiation therapy for head and neck http://www.ncbi.nlm.nih.gov/pubmed/22405807. cancer: a review of the clinical experience to date. Int J Radiat Oncol Biol Phys 2014;89:292-302. Available at: 225. Bhattasali O, Holliday E, Kies MS, et al. Definitive proton radiation http://www.ncbi.nlm.nih.gov/pubmed/24837890. therapy and concurrent cisplatin for unresectable head and neck adenoid cystic carcinoma: A series of 9 cases and a critical review of 218. Frank SJ. Intensity-modulated proton beam therapy (IMPT) versus the literature. Head Neck 2016;38 Suppl 1:E1472-1480. Available at: intensity-modulated photon therapy (IMRT). Accessed April 27, 2015.; https://www.ncbi.nlm.nih.gov/pubmed/26561041. 2015. Available at: http://clinicaltrials.gov/show/NCT01893307. 226. Patel SH, Wang Z, Wong WW, et al. Charged particle therapy 219. Miller RC, Lodge M, Murad MH, Jones B. Controversies in clinical versus photon therapy for paranasal sinus and nasal cavity malignant trials in proton radiotherapy: the present and the future. Semin Radiat diseases: a systematic review and meta-analysis. Lancet Oncol Oncol 2013;23:127-133. Available at: 2014;15:1027-1038. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23473690. http://www.ncbi.nlm.nih.gov/pubmed/24980873.

220. Zenda S, Kawashima M, Nishio T, et al. Proton beam therapy as a 227. Romesser PB, Cahlon O, Scher E, et al. Proton beam radiation nonsurgical approach to mucosal melanoma of the head and neck: a therapy results in significantly reduced toxicity compared with intensity- pilot study. Int J Radiat Oncol Biol Phys 2011;81:135-139. Available at: modulated radiation therapy for head and neck tumors that require http://www.ncbi.nlm.nih.gov/pubmed/20950948. ipsilateral radiation. Radiother Oncol 2016;118:286-292. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26867969. 221. Fukumitsu N, Okumura T, Mizumoto M, et al. Outcome of T4 (International Union Against Cancer Staging System, 7th edition) or 228. Russo AL, Adams JA, Weyman EA, et al. Long-term outcomes recurrent nasal cavity and paranasal sinus carcinoma treated with after proton beam therapy for sinonasal squamous cell carcinoma. Int J proton beam. Int J Radiat Oncol Biol Phys 2012;83:704-711. Available Radiat Oncol Biol Phys 2016;95:368-376. Available at: at: http://www.ncbi.nlm.nih.gov/pubmed/22099036. https://www.ncbi.nlm.nih.gov/pubmed/27084654.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

229. Dagan R, Bryant C, Li Z, et al. Outcomes of sinonasal cancer 236. Fitzek MM, Thornton AF, Varvares M, et al. Neuroendocrine treated with proton therapy. Int J Radiat Oncol Biol Phys 2016;95:377- tumors of the sinonasal tract. Results of a prospective study 385. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27084655. incorporating chemotherapy, surgery, and combined proton-photon radiotherapy. Cancer 2002;94:2623-2634. Available at: 230. McDonald MW, Liu Y, Moore MG, Johnstone PA. Acute toxicity in http://www.ncbi.nlm.nih.gov/pubmed/12173330. comprehensive head and neck radiation for nasopharynx and paranasal sinus cancers: cohort comparison of 3D conformal proton therapy and 237. Patel S, Kostaras X, Parliament M, et al. Recommendations for the intensity modulated radiation therapy. Radiat Oncol 2016;11:32. referral of patients for proton-beam therapy, an Alberta Health Services Available at: https://www.ncbi.nlm.nih.gov/pubmed/26922239. report: a model for Canada? Curr Oncol 2014;21:251-262. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25302033. 231. Zenda S, Kohno R, Kawashima M, et al. Proton beam therapy for unresectable malignancies of the nasal cavity and paranasal sinuses. 238. Karam I, Poon I, Lee J, et al. Stereotactic body radiotherapy for Int J Radiat Oncol Biol Phys 2011;81:1473-1478. Available at: head and neck cancer: an addition to the armamentarium against head http://www.ncbi.nlm.nih.gov/pubmed/20961697. and neck cancer. Future Oncol 2015;11:2937-2947. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26414213. 232. Santoni R, Liebsch N, Finkelstein DM, et al. Temporal lobe (TL) damage following surgery and high-dose photon and proton irradiation 239. Khan L, Tjong M, Raziee H, et al. Role of stereotactic body in 96 patients affected by chordomas and chondrosarcomas of the base radiotherapy for symptom control in head and neck cancer patients. of the skull. Int J Radiat Oncol Biol Phys 1998;41:59-68. Available at: Support Care Cancer 2015;23:1099-1103. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9588918. https://www.ncbi.nlm.nih.gov/pubmed/25294656.

233. Munzenrider JE, Liebsch NJ. Proton therapy for tumors of the skull 240. Ling DC, Vargo JA, Heron DE. Stereotactic body radiation therapy base. Strahlenther Onkol 1999;175 Suppl 2:57-63. Available at: for recurrent head and neck cancer. Cancer J 2016;22:302-306. http://www.ncbi.nlm.nih.gov/pubmed/10394399. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27441751.

234. Zenda S, Kawashima M, Arahira S, et al. Late toxicity of proton 241. Colevas AD, Read R, Thornhill J, et al. Hypothyroidism incidence beam therapy for patients with the nasal cavity, para-nasal sinuses, or after multimodality treatment for stage III and IV squamous cell involving the skull base malignancy: importance of long-term follow-up. carcinomas of the head and neck. Int J Radiat Oncol Biol Phys Int J Clin Oncol 2014. Available at: 2001;51:599-604. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25135461. http://www.ncbi.nlm.nih.gov/pubmed/11597798.

235. Chen AM, Daly ME, Bucci MK, et al. Carcinomas of the paranasal 242. Tell R, Lundell G, Nilsson B, et al. Long-term incidence of sinuses and nasal cavity treated with radiotherapy at a single institution hypothyroidism after radiotherapy in patients with head-and-neck over five decades: are we making improvement? Int J Radiat Oncol Biol cancer. Int J Radiat Oncol Biol Phys 2004;60:395-400. Available at: Phys 2007;69:141-147. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15380571. http://www.ncbi.nlm.nih.gov/pubmed/17459609. 243. Posner MR, Ervin TJ, Miller D, et al. Incidence of hypothyroidism following multimodality treatment for advanced squamous cell cancer of

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

the head and neck. Laryngoscope 1984;94:451-454. Available at: 250. Alshadwi A, Nadershah M, Carlson ER, et al. Nutritional http://www.ncbi.nlm.nih.gov/pubmed/6708688. considerations for head and neck cancer patients: a review of the literature. J Oral Maxillofac Surg 2013;71:1853-1860. Available at: 244. Cousins N, MacAulay F, Lang H, et al. A systematic review of https://www.ncbi.nlm.nih.gov/pubmed/23845698. interventions for eating and drinking problems following treatment for head and neck cancer suggests a need to look beyond swallowing and 251. Dysphagia Section OCSGMAoSCiCISoOO, Raber-Durlacher JE, trismus. Oral Oncol 2013;49:387-400. Available at: Brennan MT, et al. Swallowing dysfunction in cancer patients. Support http://www.ncbi.nlm.nih.gov/pubmed/23291294. Care Cancer 2012;20:433-443. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22205548. 245. Locher JL, Bonner JA, Carroll WR, et al. Prophylactic percutaneous endoscopic gastrostomy tube placement in treatment of 252. Wilson JA, Carding PN, Patterson JM. Dysphagia after nonsurgical head and neck cancer: a comprehensive review and call for evidence- head and neck cancer treatment: patients' perspectives. Otolaryngol based medicine. JPEN J Parenter Enteral Nutr 2011;35:365-374. Head Neck Surg 2011;145:767-771. Available at: Available at: http://www.ncbi.nlm.nih.gov/pubmed/21527598. http://www.ncbi.nlm.nih.gov/pubmed/21746839.

246. Langius JA, van Dijk AM, Doornaert P, et al. More than 10% 253. Tschiesner U. Preservation of organ function in head and neck weight loss in head and neck cancer patients during radiotherapy is cancer. GMS Curr Top Otorhinolaryngol Head Neck Surg independently associated with deterioration in quality of life. Nutr 2012;11:Doc07. Available at: Cancer 2013;65:76-83. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23320059. http://www.ncbi.nlm.nih.gov/pubmed/23368916. 254. Roe JW, Carding PN, Rhys-Evans PH, et al. Assessment and 247. August DA, Huhmann MB, American Society for P, Enteral management of dysphagia in patients with head and neck cancer who Nutrition Board of D. A.S.P.E.N. clinical guidelines: nutrition support receive radiotherapy in the United Kingdom - a web-based survey. Oral therapy during adult anticancer treatment and in hematopoietic cell Oncol 2012;48:343-348. Available at: transplantation. JPEN J Parenter Enteral Nutr 2009;33:472-500. http://www.ncbi.nlm.nih.gov/pubmed/22130454. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19713551. 255. Russi EG, Corvo R, Merlotti A, et al. Swallowing dysfunction in 248. Garg S, Yoo J, Winquist E. Nutritional support for head and neck head and neck cancer patients treated by radiotherapy: review and cancer patients receiving radiotherapy: a systematic review. Support recommendations of the supportive task group of the Italian Association Care Cancer 2010;18:667-677. Available at: of Radiation Oncology. Cancer Treat Rev 2012;38:1033-1049. Available http://www.ncbi.nlm.nih.gov/pubmed/19582484. at: http://www.ncbi.nlm.nih.gov/pubmed/22542950.

249. Rabeneck L, McCullough LB, Wray NP. Ethically justified, clinically 256. Cnossen IC, de Bree R, Rinkel RN, et al. Computerized monitoring comprehensive guidelines for percutaneous endoscopic gastrostomy of patient-reported speech and swallowing problems in head and neck tube placement. Lancet 1997;349:496-498. Available at: cancer patients in clinical practice. Support Care Cancer 2012;20:2925- http://www.ncbi.nlm.nih.gov/pubmed/9040591. 2931. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22395211.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

257. Langendijk JA, Doornaert P, Verdonck-de Leeuw IM, et al. Impact 264. Murdoch-Kinch CA, Kim HM, Vineberg KA, et al. Dose-effect of late treatment-related toxicity on quality of life among patients with relationships for the submandibular salivary glands and implications for head and neck cancer treated with radiotherapy. J Clin Oncol their sparing by intensity modulated radiotherapy. Int J Radiat Oncol 2008;26:3770-3776. Available at: Biol Phys 2008;72:373-382. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18669465. http://www.ncbi.nlm.nih.gov/pubmed/18337023.

258. Walker MP, Wichman B, Cheng AL, et al. Impact of radiotherapy 265. Little M, Schipper M, Feng FY, et al. Reducing xerostomia after dose on dentition breakdown in head and neck cancer patients. Pract chemo-IMRT for head-and-neck cancer: beyond sparing the parotid Radiat Oncol 2011;1:142-148. Available at: glands. Int J Radiat Oncol Biol Phys 2012;83:1007-1014. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21857887. http://www.ncbi.nlm.nih.gov/pubmed/22056067.

259. Jensen SB, Pedersen AM, Vissink A, et al. A systematic review of 266. Chao KS. Protection of salivary function by intensity-modulated salivary gland hypofunction and xerostomia induced by cancer radiation therapy in patients with head and neck cancer. Semin Radiat therapies: prevalence, severity and impact on quality of life. Support Oncol 2002;12:20-25. Available at: Care Cancer 2010;18:1039-1060. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11917280. http://www.ncbi.nlm.nih.gov/pubmed/20237805. 267. Murdoch-Kinch CA, Zwetchkenbaum S. Dental management of the 260. Epstein JB, Thariat J, Bensadoun RJ, et al. Oral complications of head and neck cancer patient treated with radiation therapy. J Mich cancer and cancer therapy: from cancer treatment to survivorship. CA Dent Assoc 2011;93:28-37. Available at: Cancer J Clin 2012;62:400-422. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21888251. http://www.ncbi.nlm.nih.gov/pubmed/22972543. 268. Studer G, Glanzmann C, Studer SP, et al. Risk-adapted dental 261. Deng J, Jackson L, Epstein JB, et al. Dental demineralization and care prior to intensity-modulated radiotherapy (IMRT). Schweiz caries in patients with head and neck cancer. Oral Oncol 2015;51:824- Monatsschr Zahnmed 2011;121:216-229. Available at: 831. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26198979. http://www.ncbi.nlm.nih.gov/pubmed/21534021.

262. Duarte VM, Liu YF, Rafizadeh S, et al. Comparison of dental 269. Ben-David MA, Diamante M, Radawski JD, et al. Lack of health of patients with head and neck cancer receiving IMRT vs osteoradionecrosis of the mandible after intensity-modulated conventional radiation. Otolaryngol Head Neck Surg 2014;150:81-86. radiotherapy for head and neck cancer: likely contributions of both Available at: http://www.ncbi.nlm.nih.gov/pubmed/24145147. dental care and improved dose distributions. Int J Radiat Oncol Biol Phys 2007;68:396-402. Available at: 263. Eisbruch A, Ten Haken RK, Kim HM, et al. Dose, volume, and http://www.ncbi.nlm.nih.gov/pubmed/17321069. function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat 270. Schiodt M, Hermund NU. Management of oral disease prior to Oncol Biol Phys 1999;45:577-587. Available at: radiation therapy. Support Care Cancer 2002;10:40-43. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10524409. http://www.ncbi.nlm.nih.gov/pubmed/11777187.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

271. Thariat J, Ramus L, Darcourt V, et al. Compliance with fluoride 278. Lee IJ, Koom WS, Lee CG, et al. Risk factors and dose-effect custom trays in irradiated head and neck cancer patients. Support Care relationship for mandibular osteoradionecrosis in oral and Cancer 2012;20:1811-1814. Available at: oropharyngeal cancer patients. Int J Radiat Oncol Biol Phys http://www.ncbi.nlm.nih.gov/pubmed/21947441. 2009;75:1084-1091. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19327914. 272. Horiot JC, Bone MC, Ibrahim E, Castro JR. Systematic dental management in head and neck irradiation. Int J Radiat Oncol Biol Phys 279. O'Dell K, Sinha U. Osteoradionecrosis. Oral Maxillofac Surg Clin 1981;7:1025-1029. Available at: North Am 2011;23:455-464. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7298399. http://www.ncbi.nlm.nih.gov/pubmed/21798443.

273. Sulaiman F, Huryn JM, Zlotolow IM. Dental extractions in the 280. Gevorgyan A, Wong K, Poon I, et al. Osteoradionecrosis of the irradiated head and neck patient: a retrospective analysis of Memorial mandible: a case series at a single institution. J Otolaryngol Head Neck Sloan-Kettering Cancer Center protocols, criteria, and end results. J Surg 2013;42:46. Available at: Oral Maxillofac Surg 2003;61:1123-1131. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24025531. http://www.ncbi.nlm.nih.gov/pubmed/14586845. 281. Jacobson AS, Buchbinder D, Hu K, Urken ML. Paradigm shifts in 274. Beumer J, 3rd, Harrison R, Sanders B, Kurrasch M. Postradiation the management of osteoradionecrosis of the mandible. Oral Oncol dental extractions: a review of the literature and a report of 72 episodes. 2010;46:795-801. Available at: Head Neck Surg 1983;6:581-586. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20843728. http://www.ncbi.nlm.nih.gov/pubmed/6629794. 282. Oh HK, Chambers MS, Martin JW, et al. Osteoradionecrosis of the 275. Chang DT, Sandow PR, Morris CG, et al. Do pre-irradiation dental mandible: treatment outcomes and factors influencing the progress of extractions reduce the risk of osteoradionecrosis of the mandible? Head osteoradionecrosis. J Oral Maxillofac Surg 2009;67:1378-1386. Neck 2007;29:528-536. Available at: Available at: http://www.ncbi.nlm.nih.gov/pubmed/19531406. http://www.ncbi.nlm.nih.gov/pubmed/17230555. 283. Rhodus NL, Bereuter J. Clinical evaluation of a commercially 276. Gomez DR, Estilo CL, Wolden SL, et al. Correlation of available oral moisturizer in relieving signs and symptoms of xerostomia osteoradionecrosis and dental events with dosimetric parameters in in postirradiation head and neck cancer patients and patients with intensity-modulated radiation therapy for head-and-neck cancer. Int J Sjogren's syndrome. J Otolaryngol 2000;29:28-34. Available at: Radiat Oncol Biol Phys 2011;81:e207-213. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10709169. http://www.ncbi.nlm.nih.gov/pubmed/21570202. 284. Singh ML, Papas AS. Long-term clinical observation of dental 277. Galler C, Epstein JB, Guze KA, et al. The development of caries in salivary hypofunction patients using a supersaturated calcium- osteoradionecrosis from sites of periodontal disease activity: report of 3 phosphate remineralizing rinse. J Clin Dent 2009;20:87-92. Available at: cases. J Periodontol 1992;63:310-316. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19711609. http://www.ncbi.nlm.nih.gov/pubmed/1573545. 285. Epstein JB, Schubert MM. Synergistic effect of sialagogues in management of xerostomia after radiation therapy. Oral Surg Oral Med

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Oral Pathol 1987;64:179-182. Available at: fluoride. Caries Res 1992;26:384-390. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3306552. http://www.ncbi.nlm.nih.gov/pubmed/1468104.

286. Gorsky M, Epstein JB, Parry J, et al. The efficacy of pilocarpine 293. Shulman DH, Shipman B, Willis FB. Treating trismus with dynamic and bethanechol upon saliva production in cancer patients with splinting: a case report. J Oral Sci 2009;51:141-144. Available at: hyposalivation following radiation therapy. Oral Surg Oral Med Oral http://www.ncbi.nlm.nih.gov/pubmed/19325212. Pathol Oral Radiol Endod 2004;97:190-195. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14970777. 294. Teguh DN, Levendag PC, Voet P, et al. Trismus in patients with oropharyngeal cancer: relationship with dose in structures of 287. Johnson JT, Ferretti GA, Nethery WJ, et al. Oral pilocarpine for mastication apparatus. Head Neck 2008;30:622-630. Available at: post-irradiation xerostomia in patients with head and neck cancer. N http://www.ncbi.nlm.nih.gov/pubmed/18213726. Engl J Med 1993;329:390-395. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8326972. 295. Brunello DL, Mandikos MN. The use of a dynamic opening device in the treatment of radiation induced trismus. Aust Prosthodont J 288. Dholam KP, Somani PP, Prabhu SD, Ambre SR. Effectiveness of 1995;9:45-48. Available at: fluoride varnish application as cariostatic and desensitizing agent in http://www.ncbi.nlm.nih.gov/pubmed/9063134. irradiated head and neck cancer patients. Int J Dent 2013;2013:824982. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23843793. 296. Epstein JB, Emerton S, Le ND, Stevenson-Moore P. A double- blind crossover trial of Oral Balance gel and Biotene toothpaste versus 289. Epstein JB, van der Meij EH, Lunn R, Stevenson-Moore P. Effects placebo in patients with xerostomia following radiation therapy. Oral of compliance with fluoride gel application on caries and caries risk in Oncol 1999;35:132-137. Available at: patients after radiation therapy for head and neck cancer. Oral Surg http://www.ncbi.nlm.nih.gov/pubmed/10435146. Oral Med Oral Pathol Oral Radiol Endod 1996;82:268-275. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8884824. 297. Papas A, Russell D, Singh M, et al. Caries clinical trial of a remineralising toothpaste in radiation patients. Gerodontology 290. Horiot JC, Schraub S, Bone MC, et al. Dental preservation in 2008;25:76-88. Available at: patients irradiated for head and neck tumours: A 10-year experience http://www.ncbi.nlm.nih.gov/pubmed/18485139. with topical fluoride and a randomized trial between two fluoridation methods. Radiother Oncol 1983;1:77-82. Available at: 298. McCombe D, MacGill K, Ainslie J, et al. Squamous cell carcinoma http://www.ncbi.nlm.nih.gov/pubmed/6680214. of the lip: a retrospective review of the Peter MacCallum Cancer Institute experience 1979-88. Aust N Z J Surg 2000;70:358-361. 291. Fleming TJ. Use of topical fluoride by patients receiving cancer Available at: http://www.ncbi.nlm.nih.gov/pubmed/10830600. therapy. Curr Probl Cancer 1983;7:37-41. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6851628. 299. de Visscher JG, van den Elsaker K, Grond AJ, et al. Surgical treatment of squamous cell carcinoma of the lower lip: evaluation of 292. Joyston-Bechal S, Hayes K, Davenport ES, Hardie JM. Caries long-term results and prognostic factors--a retrospective analysis of 184 incidence, mutans streptococci and lactobacilli in irradiated patients patients. J Oral Maxillofac Surg 1998;56:814-820. Available at: during a 12-month preventive programme using chlorhexidine and http://www.ncbi.nlm.nih.gov/pubmed/9663570.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

300. de Visscher JG, Botke G, Schakenraad JA, van der Waal I. A control following incomplete or inadequate excision? ANZ J Surg comparison of results after radiotherapy and surgery for stage I 2003;73:621-625. Available at: squamous cell carcinoma of the lower lip. Head Neck 1999;21:526-530. http://www.ncbi.nlm.nih.gov/pubmed/12887533. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10449668. 308. Fleming AJ, Jr., Smith SP, Jr., Paul CM, et al. Impact of [18F]-2- 301. de Visscher JG, Grond AJ, Botke G, van der Waal I. Results of fluorodeoxyglucose-positron emission tomography/computed radiotherapy for squamous cell carcinoma of the vermilion border of the tomography on previously untreated head and neck cancer patients. lower lip. A retrospective analysis of 108 patients. Radiother Oncol Laryngoscope 2007;117:1173-1179. Available at: 1996;39:9-14. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17603315. http://www.ncbi.nlm.nih.gov/pubmed/8735488. 309. van den Brekel MW, Castelijns JA, Reitsma LC, et al. Outcome of 302. Chone CT, Magalhes RS, Etchehebere E, et al. Predictive value of observing the N0 neck using ultrasonographic-guided cytology for sentinel node biopsy in head and neck cancer. Acta Otolaryngol follow-up. Arch Otolaryngol Head Neck Surg 1999;125:153-156. 2008;128:920-924. Available at: Available at: https://www.ncbi.nlm.nih.gov/pubmed/10037281. https://www.ncbi.nlm.nih.gov/pubmed/18607941. 310. Fasunla AJ, Greene BH, Timmesfeld N, et al. A meta-analysis of 303. Hokkam E, Gomaa A, Rifaat M, et al. The Role of sentinel lymph- the randomized controlled trials on elective neck dissection versus node biopsy in managing lip squamous cell carcinoma patients without therapeutic neck dissection in oral cavity cancers with clinically node- clinical evidence of nodal metastasis. Gulf J Oncolog 2013;1:57-62. negative neck. Oral Oncol 2011;47:320-324. Available at: Available at: https://www.ncbi.nlm.nih.gov/pubmed/23996868. https://www.ncbi.nlm.nih.gov/pubmed/21459661.

304. Sollamo EM, Ilmonen SK, Virolainen MS, Suominen SH. Sentinel 311. D'Cruz AK, Vaish R, Kapre N, et al. Elective versus Therapeutic lymph node biopsy in cN0 squamous cell carcinoma of the lip: A Neck Dissection in Node-Negative Oral Cancer. N Engl J Med retrospective study. Head Neck 2016;38 Suppl 1:E1375-1380. Available 2015;373:521-529. Available at: at: https://www.ncbi.nlm.nih.gov/pubmed/26514547. https://www.ncbi.nlm.nih.gov/pubmed/26027881.

305. Nag S, Cano ER, Demanes DJ, et al. The American Brachytherapy 312. Alkureishi LW, Ross GL, Shoaib T, et al. Sentinel node biopsy in Society recommendations for high-dose-rate brachytherapy for head- head and neck squamous cell cancer: 5-year follow-up of a European and-neck carcinoma. Int J Radiat Oncol Biol Phys 2001;50:1190-1198. multicenter trial. Ann Surg Oncol 2010;17:2459-2464. Available at: Available at: http://www.ncbi.nlm.nih.gov/pubmed/11483328. http://www.ncbi.nlm.nih.gov/pubmed/20552410.

306. Mazeron JJ, Ardiet JM, Haie-Meder C, et al. GEC-ESTRO 313. Civantos FJ, Zitsch RP, Schuller DE, et al. Sentinel lymph node recommendations for brachytherapy for head and neck squamous cell biopsy accurately stages the regional lymph nodes for T1-T2 oral carcinomas. Radiother Oncol 2009;91:150-156. Available at: squamous cell carcinomas: results of a prospective multi-institutional http://www.ncbi.nlm.nih.gov/pubmed/19329209. trial. J Clin Oncol 2010;28:1395-1400. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20142602. 307. Babington S, Veness MJ, Cakir B, et al. Squamous cell carcinoma of the lip: is there a role for adjuvant radiotherapy in improving local

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

314. Govers TM, Hannink G, Merkx MA, et al. Sentinel node biopsy for Head Neck Surg 2013;139:895-902. Available at: squamous cell carcinoma of the oral cavity and oropharynx: a https://www.ncbi.nlm.nih.gov/pubmed/24051744. diagnostic meta-analysis. Oral Oncol 2013;49:726-732. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23680537. 321. Branstetter BF, Blodgett TM, Zimmer LA, et al. Head and neck malignancy: is PET/CT more accurate than PET or CT alone? 315. Samant S. Sentinel node biopsy as an alternative to elective neck Radiology 2005;235:580-586. Available at: dissection for staging of early oral carcinoma. Head Neck 2014;36:241- http://www.ncbi.nlm.nih.gov/pubmed/15858097. 246. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23729239. 322. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human 316. Broglie MA, Haerle SK, Huber GF, et al. Occult metastases papillomavirus and rising oropharyngeal cancer incidence in the United detected by sentinel node biopsy in patients with early oral and States. J Clin Oncol 2011;29:4294-4301. Available at: oropharyngeal squamous cell carcinomas: impact on survival. Head http://www.ncbi.nlm.nih.gov/pubmed/21969503. Neck 2013;35:660-666. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22605675. 323. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA 2012;307:693-703. 317. Kovacs AF, Stefenelli U, Seitz O, et al. Positive sentinel lymph Available at: http://www.ncbi.nlm.nih.gov/pubmed/22282321. nodes are a negative prognostic factor for survival in T1-2 oral/oropharyngeal cancer-a long-term study on 103 patients. Ann Surg 324. Nasman A, Attner P, Hammarstedt L, et al. Incidence of human Oncol 2009;16:233-239. Available at: papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, http://www.ncbi.nlm.nih.gov/pubmed/18825461. Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009;125:362-366. Available at: 318. Pezier T, Nixon IJ, Gurney B, et al. Sentinel lymph node biopsy for http://www.ncbi.nlm.nih.gov/pubmed/19330833. T1/T2 oral cavity squamous cell carcinoma--a prospective case series. Ann Surg Oncol 2012;19:3528-3533. Available at: 325. Mehanna H, Beech T, Nicholson T, et al. Prevalence of human http://www.ncbi.nlm.nih.gov/pubmed/22411202. papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer--systematic review and meta-analysis of trends by time and 319. Agrawal A, Civantos FJ, Brumund KT, et al. [(99m)Tc]Tilmanocept region. Head Neck 2013;35:747-755. Available at: accurately detects sentinel lymph nodes and predicts node pathology https://www.ncbi.nlm.nih.gov/pubmed/22267298. status in patients with oral squamous cell carcinoma of the head and neck: results of a phase III multi-institutional trial. Ann Surg Oncol 326. Jordan RC, Lingen MW, Perez-Ordonez B, et al. Validation of 2015;22:3708-3715. Available at: methods for oropharyngeal cancer HPV status determination in US https://www.ncbi.nlm.nih.gov/pubmed/25670018. cooperative group trials. Am J Surg Pathol 2012;36:945-954. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22743284. 320. Marcinow AM, Hall N, Byrum E, et al. Use of a novel receptor- targeted (CD206) radiotracer, 99mTc-tilmanocept, and SPECT/CT for 327. Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification sentinel lymph node detection in oral cavity squamous cell carcinoma: identifies a subset of human papillomavirus--associated oropharyngeal initial institutional report in an ongoing phase 3 study. JAMA Otolaryngol cancers with favorable prognosis. J Clin Oncol 2006;24:736-747. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16401683.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

328. Cantley RL, Gabrielli E, Montebelli F, et al. Ancillary studies in 335. Ko EC, Genden EM, Misiukiewicz K, et al. Toxicity profile and determining human papillomavirus status of squamous cell carcinoma clinical outcomes in locally advanced head and neck cancer patients of the oropharynx: a review. Patholog Res Int 2011;2011:138469. treated with induction chemotherapy prior to concurrent chemoradiation. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21772959. Oncol Rep 2012;27:467-474. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22020564. 329. Singhi AD, Westra WH. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of 336. Vokes EE, Stenson K, Rosen FR, et al. Weekly carboplatin and human papillomavirus-associated head and neck cancer based on a paclitaxel followed by concomitant paclitaxel, fluorouracil, and prospective clinical experience. Cancer 2010;116:2166-2173. Available hydroxyurea chemoradiotherapy: curative and organ-preserving therapy at: https://www.ncbi.nlm.nih.gov/pubmed/20186832. for advanced head and neck cancer. J Clin Oncol 2003;21:320-326. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12525525. 330. Thavaraj S, Stokes A, Guerra E, et al. Evaluation of human papillomavirus testing for squamous cell carcinoma of the tonsil in 337. Hitt R, Grau JJ, Lopez-Pousa A, et al. A randomized phase III trial clinical practice. J Clin Pathol 2011;64:308-312. Available at: comparing induction chemotherapy followed by chemoradiotherapy https://www.ncbi.nlm.nih.gov/pubmed/21345874. versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol 2014;25:216-225. Available at: 331. Begum S, Gillison ML, Nicol TL, Westra WH. Detection of human http://www.ncbi.nlm.nih.gov/pubmed/24256848. papillomavirus-16 in fine-needle aspirates to determine tumor origin in patients with metastatic squamous cell carcinoma of the head and neck. 338. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study Clin Cancer Res 2007;13:1186-1191. Available at: comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and http://www.ncbi.nlm.nih.gov/pubmed/17317828. fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 2005;23:8636- 332. Hinni ML, Zarka MA, Hoxworth JM. Margin mapping in transoral 8645. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16275937. surgery for head and neck cancer. Laryngoscope 2013;123:1190-1198. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23382042. 339. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J 333. Cracchiolo JR, Baxi SS, Morris LG, et al. Increase in primary Med 2007;357:1705-1715. Available at: surgical treatment of T1 and T2 oropharyngeal squamous cell http://www.ncbi.nlm.nih.gov/pubmed/17960013. carcinoma and rates of adverse pathologic features: National Cancer Data Base. Cancer 2016;122:1523-1532. Available at: 340. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy http://www.ncbi.nlm.nih.gov/pubmed/26970050. added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC 334. Haughey BH, Hinni ML, Salassa JR, et al. Transoral laser Collaborative Group. Meta-Analysis of Chemotherapy on Head and microsurgery as primary treatment for advanced-stage oropharyngeal Neck Cancer. Lancet 2000;355:949-955. Available at: cancer: a United States multicenter study. Head Neck 2011;33:1683- http://www.ncbi.nlm.nih.gov/pubmed/10768432. 1694. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21284056. 341. Paccagnella A, Orlando A, Marchiori C, et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 348. Psyrri A, Rampias T, Vermorken JB. The current and future impact 1994;86:265-272. Available at: of human papillomavirus on treatment of squamous cell carcinoma of http://www.ncbi.nlm.nih.gov/pubmed/8158680. the head and neck. Ann Oncol 2014;25:2101-2115. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25057165. 342. Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in 349. Mehanna H. Update on de-intensification and intensification locally advanced squamous-cell cancer of the head and neck: long-term studies in HPV. Recent Results Cancer Res 2017;206:251-256. results of the TAX 324 randomised phase 3 trial. Lancet Oncol Available at: https://www.ncbi.nlm.nih.gov/pubmed/27699545. 2011;12:153-159. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21233014. 350. Kaczmar JM, Tan KS, Heitjan DF, et al. HPV-related oropharyngeal cancer: Risk factors for treatment failure in patients 343. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, managed with primary transoral robotic surgery. Head Neck fluorouracil, and docetaxel in unresectable head and neck cancer. N 2016;38:59-65. Available at: Engl J Med 2007;357:1695-1704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25197014. http://www.ncbi.nlm.nih.gov/pubmed/17960012. 351. Dahlstrom KR, Garden AS, William WN, Jr., et al. Proposed 344. Pignon J-P, le Maitre A, Maillard E, Bourhis J. Meta-analysis of staging system for patients with HPV-related oropharyngeal cancer chemotherapy in head and neck cancer (MACH-NC): an update on 93 based on nasopharyngeal cancer N categories. J Clin Oncol randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14. 2016;34:1848-1854. Available at: Available at: http://www.ncbi.nlm.nih.gov/pubmed/19446902. http://www.ncbi.nlm.nih.gov/pubmed/26884553.

345. Wang MB, Liu IY, Gornbein JA, Nguyen CT. HPV-positive 352. Gillison ML. Human papillomavirus and oropharyngeal cancer oropharyngeal carcinoma: a systematic review of treatment and stage. J Clin Oncol 2016;34:1833-1835. Available at: prognosis. Otolaryngol Head Neck Surg 2015;153:758-769. Available https://www.ncbi.nlm.nih.gov/pubmed/27114590. at: https://www.ncbi.nlm.nih.gov/pubmed/26124261. 353. Quon H, Forastiere AA. Controversies in treatment 346. RTOG 0522: a randomized phase III trial of concurrent accelerated deintensification of human papillomavirus-associated oropharyngeal radiation and cisplatin versus concurrent accelerated radiation, cisplatin, carcinomas: should we, how should we, and for whom? J Clin Oncol and cetuximab [followed by surgery for selected patients] for Stage III 2013;31:520-522. Available at: and IV head and neck carcinomas. Clin Adv Hematol Oncol 2007;5:79- http://www.ncbi.nlm.nih.gov/pubmed/23295808. 81. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17344795. 354. Masterson L, Moualed D, Masood A, et al. De-escalation treatment 347. Argiris A, Li S, Ghebremichael M, et al. Prognostic significance of protocols for human papillomavirus-associated oropharyngeal human papillomavirus in recurrent or metastatic head and neck cancer: squamous cell carcinoma. Cochrane Database Syst Rev an analysis of Eastern Cooperative Oncology Group trials. Ann Oncol 2014;2:CD010271. Available at: 2014;25:1410-1416. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24532092. https://www.ncbi.nlm.nih.gov/pubmed/24799460.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

355. Kofler B, Laban S, Busch CJ, et al. New treatment strategies for oropharynx cancer. Oral Oncol 2015;51:514-520. Available at: HPV-positive head and neck cancer. Eur Arch Otorhinolaryngol https://www.ncbi.nlm.nih.gov/pubmed/25771076. 2014;271:1861-1867. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23934317. 362. Geiger JL, Lazim AF, Walsh FJ, et al. Adjuvant chemoradiation therapy with high-dose versus weekly cisplatin for resected, locally- 356. Marur S, Li S, Cmelak AJ, et al. E1308: phase II trial of induction advanced HPV/p16-positive and negative head and neck squamous cell chemotherapy followed by reduced-dose radiation and weekly carcinoma. Oral Oncol 2014;50:311-318. Available at: cetuximab in patients with HPV-associated resectable squamous cell https://www.ncbi.nlm.nih.gov/pubmed/24467937. carcinoma of the oropharynx- ECOG-ACRIN Cancer Research Group. J Clin Oncol 2016:Jco2016683300. Available at: 363. Sinha P, Lewis JS, Jr., Kallogjeri D, et al. Soft tissue metastasis in https://www.ncbi.nlm.nih.gov/pubmed/28029303. p16-positive oropharynx carcinoma: Prevalence and association with distant metastasis. Oral Oncol 2015;51:778-786. Available at: 357. Sinha P, Piccirillo JF, Kallogjeri D, et al. The role of postoperative https://www.ncbi.nlm.nih.gov/pubmed/26033471. chemoradiation for oropharynx carcinoma: a critical appraisal of the published literature and National Comprehensive Cancer Network 364. Mehra R, Ang KK, Burtness B. Management of human guidelines. Cancer 2015;121:1747-1754. Available at: papillomavirus-positive and human papillomavirus-negative head and https://www.ncbi.nlm.nih.gov/pubmed/25588360. neck cancer. Semin Radiat Oncol 2012;22:194-197. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22687943. 358. Cooper JS, Fortpied C, Gregoire V, et al. The role of postoperative chemoradiation for oropharynx carcinoma: A critical appraisal revisited. 365. Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in Cancer 2017;123:12-16. Available at: pyriform sinus cancer: preliminary results of a European Organization https://www.ncbi.nlm.nih.gov/pubmed/27727449. for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996;88:890-899. 359. Iyer NG, Dogan S, Palmer F, et al. Detailed analysis of Available at: http://www.ncbi.nlm.nih.gov/pubmed/8656441. clinicopathologic factors demonstrate distinct difference in outcome and prognostic factors between surgically treated HPV-positive and negative 366. Induction chemotherapy plus radiation compared with surgery plus oropharyngeal cancer. Ann Surg Oncol 2015;22:4411-4421. Available radiation in patients with advanced laryngeal cancer. The Department of at: https://www.ncbi.nlm.nih.gov/pubmed/25801358. Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324:1685-1690. Available at: 360. Maxwell JH, Ferris RL, Gooding W, et al. Extracapsular spread in http://www.ncbi.nlm.nih.gov/pubmed/2034244. head and neck carcinoma: impact of site and human papillomavirus status. Cancer 2013;119:3302-3308. Available at: 367. McNeil BJ, Weichselbaum R, Pauker SG. Speech and survival: https://www.ncbi.nlm.nih.gov/pubmed/23797868. tradeoffs between quality and quantity of life in laryngeal cancer. N Engl J Med 1981;305:982-987. Available at: 361. Sinha P, Kallogjeri D, Gay H, et al. High metastatic node number, http://www.ncbi.nlm.nih.gov/pubmed/7278922. not extracapsular spread or N-classification is a node-related prognosticator in transorally-resected, neck-dissected p16-positive 368. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

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373. Merlano M, Benasso M, Corvo R, et al. Five-year update of a 380. Hanna GJ, Haddad RI, Lorch JH. Induction chemotherapy for randomized trial of alternating radiotherapy and chemotherapy locoregionally advanced head and neck cancer: past, present, future? compared with radiotherapy alone in treatment of unresectable Oncologist 2013;18:288-293. Available at: squamous cell carcinoma of the head and neck. J Natl Cancer Inst http://www.ncbi.nlm.nih.gov/pubmed/23442306. 1996;88:583-589. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8609658. 381. Argiris A, Haraf DJ, Kies MS, Vokes EE. Intensive concurrent chemoradiotherapy for head and neck cancer with 5-Fluorouracil- and 374. Wendt TG, Grabenbauer GG, Rodel CM, et al. Simultaneous hydroxyurea-based regimens: reversing a pattern of failure. Oncologist radiochemotherapy versus radiotherapy alone in advanced head and 2003;8:350-360. Available at: neck cancer: a randomized multicenter study. J Clin Oncol http://www.ncbi.nlm.nih.gov/pubmed/12897332. 1998;16:1318-1324. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9552032.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

382. Machtay M, Moughan J, Farach A, et al. Hypopharyngeal dose is advanced head and neck cancer: a phase II randomized study. Ann associated with severe late toxicity in locally advanced head-and-neck Oncol 2010;21:1515-1522. Available at: cancer: an RTOG analysis. Int J Radiat Oncol Biol Phys 2012;84:983- http://www.ncbi.nlm.nih.gov/pubmed/20032123. 989. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23078898. 389. Ghi MG, Paccagnella A, Ferrari D, et al. Concomitant 383. Janoray G, Pointreau Y, Garaud P, et al. Long-term results of a chemoradiation (CRT) or cetuximab/RT (CET/RT) versus induction multicenter randomized phase III trial of induction chemotherapy with Docetaxel/ Cisplatin/5-Fluorouracil (TPF) followed by CRT or CET/RT in cisplatin, 5-fluorouracil, +/- docetaxel for larynx preservation. J Natl patients with Locally Advanced Squamous Cell Carcinoma of Head and Cancer Inst 2016;108. Available at: Neck (LASCCHN). A randomized phase III factorial study https://www.ncbi.nlm.nih.gov/pubmed/26681800. (NCT01086826) [abstract]. J Clin Oncol 2014;32:Abstract 6004. Available at: http://meetinglibrary.asco.org/content/129831-144. 384. Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without 390. Wanebo HJ, Lee J, Burtness BA, et al. Induction cetuximab, docetaxel for larynx preservation. J Natl Cancer Inst 2009;101:498-506. paclitaxel, and carboplatin followed by chemoradiation with cetuximab, Available at: http://www.ncbi.nlm.nih.gov/pubmed/19318632. paclitaxel, and carboplatin for stage III/IV head and neck squamous cancer: a phase II ECOG-ACRIN trial (E2303). Ann Oncol 385. Blanchard P, Bourhis J, Lacas B, et al. Taxane-cisplatin- 2014;25:2036-2041. Available at: fluorouracil as induction chemotherapy in locally advanced head and https://www.ncbi.nlm.nih.gov/pubmed/25009013. neck cancers: an individual patient data meta-analysis of the meta- analysis of chemotherapy in head and neck cancer group. J Clin Oncol 391. Semrau S, Schmidt D, Lell M, et al. Results of chemoselection with 2013;31:2854-2860. Available at: short induction chemotherapy followed by chemoradiation or surgery in https://www.ncbi.nlm.nih.gov/pubmed/23835714. the treatment of functionally inoperable carcinomas of the pharynx and larynx. Oral Oncol 2013;49:454-460. Available at: 386. Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy https://www.ncbi.nlm.nih.gov/pubmed/23321550. followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in 392. Buiret G, Combe C, Favrel V, et al. A retrospective, multicenter locally advanced head and neck cancer (PARADIGM): a randomised study of the tolerance of induction chemotherapy with docetaxel, phase 3 trial. Lancet Oncol 2013;14:257-264. Available at: Cisplatin, and 5-Fluorouracil followed by radiotherapy with concomitant http://www.ncbi.nlm.nih.gov/pubmed/23414589. cetuximab in 46 cases of squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2010;77:430-437. Available at: 387. Cohen EE, Karrison TG, Kocherginsky M, et al. Phase III http://www.ncbi.nlm.nih.gov/pubmed/19775831. randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol 2014;32:2735- 393. Lefebvre JL, Pointreau Y, Rolland F, et al. Induction chemotherapy 2743. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25049329. followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol 388. Paccagnella A, Ghi MG, Loreggian L, et al. Concomitant 2013;31:853-859. Available at: chemoradiotherapy versus induction docetaxel, cisplatin and 5 http://www.ncbi.nlm.nih.gov/pubmed/23341517. fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

394. Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, et al. 401. Cooper JS, del Rowe J, Newall J. Regional stage IV carcinoma of Chemoradiation comparing cisplatin versus carboplatin in locally the nasopharynx treated by aggressive radiotherapy. Int J Radiat Oncol advanced nasopharyngeal cancer: randomised, non-inferiority, open Biol Phys 1983;9:1737-1745. Available at: trial. Eur J Cancer 2007;43:1399-1406. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6417075. http://www.ncbi.nlm.nih.gov/pubmed/17467265. 402. Bailet JW, Mark RJ, Abemayor E, et al. Nasopharyngeal 395. Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus carcinoma: treatment results with primary radiation therapy. radiotherapy in patients with advanced nasopharyngeal cancer: phase Laryngoscope 1992;102:965-972. Available at: III randomized Intergroup study 0099. J Clin Oncol 1998;16:1310-1317. http://www.ncbi.nlm.nih.gov/pubmed/1518360. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9552031. 403. Johansen LV, Mestre M, Overgaard J. Carcinoma of the 396. Garden AS, Kies MS, Morrison WH, et al. Outcomes and patterns nasopharynx: analysis of treatment results in 167 consecutively of care of patients with locally advanced oropharyngeal carcinoma admitted patients. Head Neck 1992;14:200-207. Available at: treated in the early 21st century. Radiat Oncol 2013;8:21. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1587737. http://www.ncbi.nlm.nih.gov/pubmed/23360540. 404. Sanguineti G, Geara FB, Garden AS, et al. Carcinoma of the 397. Al-Mamgani A, Van Rooij P, Tans L, et al. Toxicity and outcome of nasopharynx treated by radiotherapy alone: determinants of local and intensity-modulated radiotherapy versus 3-dimensional conformal regional control. Int J Radiat Oncol Biol Phys 1997;37:985-996. radiotherapy for oropharyngeal cancer: a matched-pair analysis. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9169804. Technol Cancer Res Treat 2013;12:123-130. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23098281. 405. Wang C. Radiation Therapy for Head and Neck Neoplasms, 3rd ed. New York: Wiley-Liss; 1997. 398. Eisbruch A, Harris J, Garden AS, et al. Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for 406. Lewis JS, Jr., Chernock RD. Human papillomavirus and Epstein early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol Barr virus in head and neck carcinomas: suggestions for the new WHO Biol Phys 2010;76:1333-1338. Available at: classification. Head Neck Pathol 2014;8:50-58. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19540060. https://www.ncbi.nlm.nih.gov/pubmed/24595417.

399. Kotwall C, Sako K, Razack MS, et al. Metastatic patterns in 407. Banko AV, Lazarevic IB, Folic MM, et al. Characterization of the squamous cell cancer of the head and neck. Am J Surg 1987;154:439- variability of Epstein-Barr virus genes in nasopharyngeal biopsies: 442. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3661849. potential predictors for carcinoma progression. PLoS One 2016;11:e0153498. Available at: 400. Lefebvre JL, Rolland F, Tesselaar M, et al. Phase 3 randomized https://www.ncbi.nlm.nih.gov/pubmed/27071030. trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst 2009;101:142-152. 408. Gulley ML, Tang W. Laboratory assays for Epstein-Barr virus- Available at: http://www.ncbi.nlm.nih.gov/pubmed/19176454. related disease. J Mol Diagn 2008;10:279-292. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18556771.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

409. Lin JC, Wang WY, Chen KY, et al. Quantification of plasma 416. Jeon YK, Lee BY, Kim JE, et al. Molecular characterization of Epstein-Barr virus DNA in patients with advanced nasopharyngeal Epstein-Barr virus and oncoprotein expression in nasopharyngeal carcinoma. N Engl J Med 2004;350:2461-2470. Available at: carcinoma in Korea. Head Neck 2004;26:573-583. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15190138. https://www.ncbi.nlm.nih.gov/pubmed/15229899.

410. Chan AT, Lo YM, Zee B, et al. Plasma Epstein-Barr virus DNA and 417. Gulley ML. Molecular diagnosis of Epstein-Barr virus-related residual disease after radiotherapy for undifferentiated nasopharyngeal diseases. J Mol Diagn 2001;3:1-10. Available at: carcinoma. J Natl Cancer Inst 2002;94:1614-1619. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11227065. https://www.ncbi.nlm.nih.gov/pubmed/12419787. 418. Mesic JB, Fletcher GH, Goepfert H. Megavoltage irradiation of 411. Lin JC, Wang WY, Liang WM, et al. Long-term prognostic effects epithelial tumors of the nasopharynx. Int J Radiat Oncol Biol Phys of plasma epstein-barr virus DNA by minor groove binder-probe real- 1981;7:447-453. Available at: time quantitative PCR on nasopharyngeal carcinoma patients receiving http://www.ncbi.nlm.nih.gov/pubmed/6788731. concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007;68:1342-1348. Available at: 419. Hoppe RT, Goffinet DR, Bagshaw MA. Carcinoma of the https://www.ncbi.nlm.nih.gov/pubmed/17449194. nasopharynx. Eighteen years' experience with megavoltage radiation therapy. Cancer 1976;37:2605-2612. Available at: 412. Zhang W, Chen Y, Chen L, et al. The clinical utility of plasma http://www.ncbi.nlm.nih.gov/pubmed/820419. Epstein-Barr virus DNA assays in nasopharyngeal carcinoma: the dawn of a new era?: a systematic review and meta-analysis of 7836 cases. 420. Blanchard P, Lee A, Marguet S, et al. Chemotherapy and Medicine (Baltimore) 2015;94:e845. Available at: radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC https://www.ncbi.nlm.nih.gov/pubmed/25997061. meta-analysis. Lancet Oncol 2015;16:645-655. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25957714. 413. Peng H, Guo R, Chen L, et al. Prognostic impact of plasma Epstein-Barr virus DNA in patients with nasopharyngeal carcinoma 421. Wang Y, Ding W, Chen C, et al. Meta-analysis of concurrent treated using intensity-modulated radiation therapy. Sci Rep chemoradiotherapy in the treatment of locoregionally advanced 2016;6:22000. Available at: nasopharyngeal carcinoma. J Cancer Res Ther 2015;11 Suppl 2:C191- https://www.ncbi.nlm.nih.gov/pubmed/26924234. 195. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26506874.

414. Zhang J, Shu C, Song Y, et al. Epstein-Barr virus DNA level as a 422. Wee J, Tan EH, Tai BC, et al. Randomized trial of radiotherapy novel prognostic factor in nasopharyngeal carcinoma: A meta-analysis. versus concurrent chemoradiotherapy followed by adjuvant Medicine (Baltimore) 2016;95:e5130. Available at: chemotherapy in patients with American Joint Committee on https://www.ncbi.nlm.nih.gov/pubmed/27749596. Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 415. Zeng Z, Fan S, Zhang X, et al. Epstein-Barr virus-encoded small 2005;23:6730-6738. Available at: RNA 1 (EBER-1) could predict good prognosis in nasopharyngeal http://www.ncbi.nlm.nih.gov/pubmed/16170180. carcinoma. Clin Transl Oncol 2016;18:206-211. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26260913.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

423. Chan AT, Leung SF, Ngan RK, et al. Overall survival after Cancer Chemother Pharmacol 2010;65:589-595. Available at: concurrent cisplatin-radiotherapy compared with radiotherapy alone in http://www.ncbi.nlm.nih.gov/pubmed/19830427. locoregionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2005;97:536-539. Available at: 430. Sun Y, Li WF, Chen NY, et al. Induction chemotherapy plus http://www.ncbi.nlm.nih.gov/pubmed/15812080. concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 424. Wu X, Huang PY, Peng PJ, et al. Long-term follow-up of a phase 3, multicentre, randomised controlled trial. Lancet Oncol 2016;17:1509- III study comparing radiotherapy with or without weekly oxaliplatin for 1520. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27686945. locoregionally advanced nasopharyngeal carcinoma. Ann Oncol 2013;24:2131-2136. Available at: 431. Hui EP, Ma BB, Leung SF, et al. Randomized phase II trial of https://www.ncbi.nlm.nih.gov/pubmed/23661293. concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol 425. Ribassin-Majed L, Marguet S, Lee AW, et al. What is the best 2009;27:242-249. Available at: treatment of locally advanced nasopharyngeal carcinoma? An individual http://www.ncbi.nlm.nih.gov/pubmed/19064973. patient data network meta-analysis. J Clin Oncol 2016:Jco2016674119. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27918720. 432. Rodel RM, Steiner W, Muller RM, et al. Endoscopic laser surgery of early glottic cancer: involvement of the anterior commissure. Head 426. Yan M, Kumachev A, Siu LL, Chan KK. Chemoradiotherapy Neck 2009;31:583-592. Available at: regimens for locoregionally advanced nasopharyngeal carcinoma: A http://www.ncbi.nlm.nih.gov/pubmed/19132720. Bayesian network meta-analysis. Eur J Cancer 2015;51:1570-1579. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26044925. 433. Zouhair A, Azria D, Coucke P, et al. Decreased local control following radiation therapy alone in early-stage glottic carcinoma with 427. Chen L, Hu CS, Chen XZ, et al. Concurrent chemoradiotherapy anterior commissure extension. Strahlenther Onkol 2004;180:84-90. plus adjuvant chemotherapy versus concurrent chemoradiotherapy Available at: http://www.ncbi.nlm.nih.gov/pubmed/14762660. alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Lancet 434. Silver CE, Beitler JJ, Shaha AR, et al. Current trends in initial Oncol 2012;13:163-171. Available at: management of laryngeal cancer: the declining use of open surgery. http://www.ncbi.nlm.nih.gov/pubmed/22154591. Eur Arch Otorhinolaryngol 2009;266:1333-1352. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19597837. 428. Dechaphunkul T, Pruegsanusak K, Sangthawan D, Sunpaweravong P. Concurrent chemoradiotherapy with carboplatin 435. Warner L, Chudasama J, Kelly CG, et al. Radiotherapy versus followed by carboplatin and 5-fluorouracil in locally advanced open surgery versus endolaryngeal surgery (with or without laser) for nasopharyngeal carcinoma. Head Neck Oncol 2011;3:30. Available at: early laryngeal squamous cell cancer. Cochrane Database Syst Rev http://www.ncbi.nlm.nih.gov/pubmed/21639934. 2014:Cd002027. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25503538. 429. Bae WK, Hwang JE, Shim HJ, et al. Phase II study of docetaxel, cisplatin, and 5-FU induction chemotherapy followed by 436. Yoo J, Lacchetti C, Hammond JA, Gilbert RW. Role of chemoradiotherapy in locoregionally advanced nasopharyngeal cancer. endolaryngeal surgery (with or without laser) versus radiotherapy in the

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

management of early (T1) glottic cancer: a systematic review. Head 444. Oprea C, Cainap C, Azoulay R, et al. Primary diffuse large B-cell Neck 2014;36:1807-1819. Available at: non-Hodgkin lymphoma of the paranasal sinuses: a report of 14 cases. https://www.ncbi.nlm.nih.gov/pubmed/24115131. Br J Haematol 2005;131:468-471. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16281936. 437. Stokes WA, Jones BL, Bhatia S, et al. A comparison of overall survival for patients with T4 larynx cancer treated with surgical versus 445. Cantu G, Bimbi G, Miceli R, et al. Lymph node metastases in organ-preservation approaches: A National Cancer Data Base analysis. malignant tumors of the paranasal sinuses: prognostic value and Cancer 2017;123:600-608. Available at: treatment. Arch Otolaryngol Head Neck Surg 2008;134:170-177. https://www.ncbi.nlm.nih.gov/pubmed/27727461. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18283160.

438. Katz TS, Mendenhall WM, Morris CG, et al. Malignant tumors of 446. Al-Mamgani A, van Rooij P, Mehilal R, et al. Combined-modality the nasal cavity and paranasal sinuses. Head Neck 2002;24:821-829. treatment improved outcome in sinonasal undifferentiated carcinoma: Available at: http://www.ncbi.nlm.nih.gov/pubmed/12211046. single-institutional experience of 21 patients and review of the literature. Eur Arch Otorhinolaryngol 2013;270:293-299. Available at: 439. Cohen ZR, Marmor E, Fuller GN, DeMonte F. Misdiagnosis of http://www.ncbi.nlm.nih.gov/pubmed/22476411. olfactory neuroblastoma. Neurosurg Focus 2002;12:e3. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16119901. 447. Mourad WF, Hauerstock D, Shourbaji RA, et al. Trimodality Management of Sinonasal Undifferentiated Carcinoma and Review of 440. Ejaz A, Wenig BM. Sinonasal undifferentiated carcinoma: clinical the Literature. Am J Clin Oncol 2013;36:584-588. Available at: and pathologic features and a discussion on classification, cellular http://www.ncbi.nlm.nih.gov/pubmed/22992621. differentiation, and differential diagnosis. Adv Anat Pathol 2005;12:134- 143. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15900114. 448. Lin EM, Sparano A, Spalding A, et al. Sinonasal undifferentiated carcinoma: a 13-year experience at a single institution. Skull Base 441. Iezzoni JC, Mills SE. "Undifferentiated" small round cell tumors of 2010;20:61-67. Available at: the sinonasal tract: differential diagnosis update. Am J Clin Pathol http://www.ncbi.nlm.nih.gov/pubmed/20808529. 2005;124 Suppl:110-121. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16468421. 449. Babin E, Rouleau V, Vedrine PO, et al. Small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses. J Laryngol Otol 442. Dulguerov P, Jacobsen MS, Allal AS, et al. Nasal and paranasal 2006;120:289-297. Available at: sinus carcinoma: are we making progress? A series of 220 patients and http://www.ncbi.nlm.nih.gov/pubmed/16526967. a systematic review. Cancer 2001;92:3012-3029. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11753979. 450. Chen AM, Daly ME, El-Sayed I, et al. Patterns of failure after combined-modality approaches incorporating radiotherapy for sinonasal 443. Munoz J, Kuriakose P. Antibiotic-refractory sinusitis. JAMA undifferentiated carcinoma of the head and neck. Int J Radiat Oncol Biol 2012;308:2399-2400. Available at: Phys 2008;70:338-343. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23232896. http://www.ncbi.nlm.nih.gov/pubmed/18207030.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

451. Mendenhall WM, Mendenhall CM, Riggs CE, Jr., et al. Sinonasal 459. Kondo N, Takahashi H, Nii Y, Nagao J. Olfactory neuroblastoma: undifferentiated carcinoma. Am J Clin Oncol 2006;29:27-31. Available 15 years of experience. Anticancer Res 2012;32:1697-1703. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16462499. at: http://www.ncbi.nlm.nih.gov/pubmed/22593448.

452. Kim BS, Vongtama R, Juillard G. Sinonasal undifferentiated 460. Ozsahin M, Gruber G, Olszyk O, et al. Outcome and prognostic carcinoma: case series and literature review. Am J Otolaryngol factors in olfactory neuroblastoma: a rare cancer network study. Int J 2004;25:162-166. Available at: Radiat Oncol Biol Phys 2010;78:992-997. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15124164. http://www.ncbi.nlm.nih.gov/pubmed/20231062.

453. Smith SR, Som P, Fahmy A, et al. A clinicopathological study of 461. de Gabory L, Abdulkhaleq HM, Darrouzet V, et al. Long-term sinonasal neuroendocrine carcinoma and sinonasal undifferentiated results of 28 esthesioneuroblastomas managed over 35 years. Head carcinoma. Laryngoscope 2000;110:1617-1622. Available at: Neck 2011;33:82-86. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11037813. http://www.ncbi.nlm.nih.gov/pubmed/20848423.

454. Diaz EM, Johnigan RH, Pero C, et al. Olfactory neuroblastoma: the 462. Bachar G, Goldstein DP, Shah M, et al. Esthesioneuroblastoma: 22-year experience at one comprehensive cancer center. Head Neck The Princess Margaret Hospital experience. Head Neck 2008;30:1607- 2005;27:138-149. Available at: 1614. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18798301. http://www.ncbi.nlm.nih.gov/pubmed/15654688. 463. Dirix P, Nuyts S, Geussens Y, et al. Malignancies of the nasal 455. McLean JN, Nunley SR, Klass C, et al. Combined modality therapy cavity and paranasal sinuses: long-term outcome with conventional or of esthesioneuroblastoma. Otolaryngol Head Neck Surg 2007;136:998- three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 1002. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17547995. 2007;69:1042-1050. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17570610. 456. Ow TJ, Bell D, Kupferman ME, et al. Esthesioneuroblastoma. Neurosurg Clin N Am 2013;24:51-65. Available at: 464. Hoppe BS, Stegman LD, Zelefsky MJ, et al. Treatment of nasal http://www.ncbi.nlm.nih.gov/pubmed/23174357. cavity and paranasal sinus cancer with modern radiotherapy techniques in the postoperative setting--the MSKCC experience. Int J Radiat Oncol 457. Song CM, Won TB, Lee CH, et al. Treatment modalities and Biol Phys 2007;67:691-702. Available at: outcomes of olfactory neuroblastoma. Laryngoscope 2012;122:2389- http://www.ncbi.nlm.nih.gov/pubmed/17161557. 2395. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23070733. 465. Porceddu S, Martin J, Shanker G, et al. Paranasal sinus tumors: 458. Sohrabi S, Drabick JJ, Crist H, et al. Neoadjuvant concurrent Peter MacCallum Cancer Institute experience. Head Neck 2004;26:322- chemoradiation for advanced esthesioneuroblastoma: a case series and 330. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15054735. review of the literature. J Clin Oncol 2011;29:e358-361. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21282533. 466. Le QT, Fu KK, Kaplan MJ, et al. Lymph node metastasis in maxillary sinus carcinoma. Int J Radiat Oncol Biol Phys 2000;46:541- 549. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10701732.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

467. Al-Mamgani A, Monserez D, Rooij P, et al. Highly-conformal 474. Jin Y, Cai XY, Shi YX, et al. Comparison of five cisplatin-based intensity-modulated radiotherapy reduced toxicity without jeopardizing regimens frequently used as the first-line protocols in metastatic outcome in patients with paranasal sinus cancer treated by surgery and nasopharyngeal carcinoma. J Cancer Res Clin Oncol 2012;138:1717- radiotherapy or (chemo)radiation. Oral Oncol 2012;48:905-911. 1725. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22684794. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22584070. 475. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based 468. Dirix P, Vanstraelen B, Jorissen M, et al. Intensity-modulated chemotherapy plus cetuximab in head and neck cancer. N Engl J Med radiotherapy for sinonasal cancer: improved outcome compared to 2008;359:1116-1127. Available at: conventional radiotherapy. Int J Radiat Oncol Biol Phys 2010;78:998- http://www.ncbi.nlm.nih.gov/pubmed/18784101. 1004. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20338694. 476. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab 469. Hoppe BS, Nelson CJ, Gomez DR, et al. Unresectable carcinoma for squamous-cell carcinoma of the head and neck. N Engl J Med of the paranasal sinuses: outcomes and toxicities. Int J Radiat Oncol 2006;354:567-578. Available at: Biol Phys 2008;72:763-769. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16467544. http://www.ncbi.nlm.nih.gov/pubmed/18395361. 477. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab 470. Hoppe BS, Wolden SL, Zelefsky MJ, et al. Postoperative intensity- for locoregionally advanced head and neck cancer: 5-year survival data modulated radiation therapy for cancers of the paranasal sinuses, nasal from a phase 3 randomised trial, and relation between cetuximab- cavity, and lacrimal glands: technique, early outcomes, and toxicity. induced rash and survival. Lancet Oncol 2010;11:21-28. Available at: Head Neck 2008;30:925-932. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19897418. http://www.ncbi.nlm.nih.gov/pubmed/18302261. 478. Bonner J, Giralt J, Harari P, et al. Cetuximab and radiotherapy in 471. Guigay J, Fayette J, Dillies A-F, et al. Cetuximab, docetaxel, and laryngeal preservation for cancers of the larynx and hypopharynx: a cisplatin (TPEx) as first-line treatment in patients with recurrent or secondary analysis of a randomized clinical trial. JAMA Otolaryngol metastatic (R/M) squamous cell carcinoma of the head and neck Head Neck Surg 2016;142:842-849. Available at: (SCCHN): Final results of phase II trial GORTEC 2008-03 [abstract]. J https://www.ncbi.nlm.nih.gov/pubmed/27389475. Clin Oncol 2012;30(Suppl 15):Abstract 5505. Available at: http://meeting.ascopubs.org/cgi/content/abstract/30/15_suppl/5505. 479. Garden AS, Harris J, Vokes EE, et al. Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized phase II trial 472. Price KA, Cohen EE. Current treatment options for metastatic head of concurrent radiation and chemotherapy for advanced squamous cell and neck cancer. Curr Treat Options Oncol 2012;13:35-46. Available at: carcinomas of the head and neck. J Clin Oncol 2004;22:2856-2864. http://www.ncbi.nlm.nih.gov/pubmed/22252884. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15254053.

473. Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study 480. Garden AS, Harris J, Vokes EE, et al. Results of Radiation of the epidermal growth factor receptor antibody cetuximab and cisplatin Therapy Oncology Group 97-03—A randomized phase II trial of for recurrent and refractory squamous cell carcinoma of the head and concurrent radiation and chemotherapy for advanced squamous cell neck. J Clin Oncol 2005;23:5578-5587. Available at: carcinomas of the head and neck: Long-term results and late toxicities http://www.ncbi.nlm.nih.gov/pubmed/16009949. [abstract]. Int J Radiat Oncol Biol Phys 2007;69:S140. Available at:

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

http://linkinghub.elsevier.com/retrieve/pii/S036030160701019X?showall metastatic/recurrent head and neck cancer: an Eastern Cooperative =true. Oncology Group study. J Clin Oncol 2005;23:8646-8654. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16314626. 481. Magrini SM, Buglione M, Corvo R, et al. Cetuximab and radiotherapy versus cisplatin and radiotherapy for locally advanced 488. Grau JJ, Caballero M, Verger E, et al. Weekly paclitaxel for platin- head and neck cancer: a randomized phase II trial. J Clin Oncol resistant stage IV head and neck cancer patients. Acta Otolaryngol 2016;34:427-435. Available at: 2009;129:1294-1299. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26644536. http://www.ncbi.nlm.nih.gov/pubmed/19863327.

482. Ang KK, Zhang Q, Rosenthal DI, et al. Randomized phase III trial 489. Guardiola E, Peyrade F, Chaigneau L, et al. Results of a of concurrent accelerated radiation plus cisplatin with or without randomised phase II study comparing docetaxel with methotrexate in cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J patients with recurrent head and neck cancer. Eur J Cancer Clin Oncol 2014;32:2940-2950. Available at: 2004;40:2071-2076. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25154822. http://www.ncbi.nlm.nih.gov/pubmed/15341981.

483. Fury MG, Pfister DG. Current recommendations for systemic 490. Catimel G, Verweij J, Mattijssen V, et al. Docetaxel (Taxotere): an therapy of recurrent and/or metastatic head and neck squamous cell active drug for the treatment of patients with advanced squamous cell cancer. J Natl Compr Canc Netw 2011;9:681-689. Available at: carcinoma of the head and neck. EORTC Early Clinical Trials Group. http://www.ncbi.nlm.nih.gov/pubmed/21636539. Ann Oncol 1994;5:533-537. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7918125. 484. Molin Y, Fayette J. Current chemotherapies for recurrent/metastatic head and neck cancer. Anticancer Drugs 491. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib 2011;22:621-625. Available at: compared with intravenous methotrexate for recurrent squamous cell http://www.ncbi.nlm.nih.gov/pubmed/21131821. carcinoma of the head and neck [corrected]. J Clin Oncol 2009;27:1864- 1871. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19289630. 485. Hoffmann TK. Systemic therapy strategies for head-neck carcinomas: Current status. GMS Curr Top Otorhinolaryngol Head Neck 492. Forastiere AA, Metch B, Schuller DE, et al. Randomized Surg 2012;11:Doc03. Available at: comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil http://www.ncbi.nlm.nih.gov/pubmed/23320055. versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 486. Jacobs C, Lyman G, Velez-Garcia E, et al. A phase III randomized 1992;10:1245-1251. Available at: study comparing cisplatin and fluorouracil as single agents and in http://www.ncbi.nlm.nih.gov/pubmed/1634913. combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992;10:257-263. Available at: 493. Haigentz M, Jr., Hartl DM, Silver CE, et al. Distant metastases http://www.ncbi.nlm.nih.gov/pubmed/1732427. from head and neck squamous cell carcinoma. Part III. Treatment. Oral Oncol 2012;48:787-793. Available at: 487. Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized http://www.ncbi.nlm.nih.gov/pubmed/22516376. trial of cisplatin plus placebo compared with cisplatin plus cetuximab in

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

494. Martinez-Trufero J, Isla D, Adansa JC, et al. Phase II study of 500. Colevas AD. Chemotherapy options for patients with metastatic or capecitabine as palliative treatment for patients with recurrent and recurrent squamous cell carcinoma of the head and neck. J Clin Oncol metastatic squamous head and neck cancer after previous platinum- 2006;24:2644-2652. Available at: based treatment. Br J Cancer 2010;102:1687-1691. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16763278. http://www.ncbi.nlm.nih.gov/pubmed/20485287. 501. Forastiere AA, Shank D, Neuberg D, et al. Final report of a phase 495. Eschwege F, Sancho-Garnier H, Gerard JP, et al. Ten-year results II evaluation of paclitaxel in patients with advanced squamous cell of randomized trial comparing radiotherapy and concomitant bleomycin carcinoma of the head and neck: an Eastern Cooperative Oncology to radiotherapy alone in epidermoid carcinomas of the oropharynx: Group trial (PA390). Cancer 1998;82:2270-2274. Available at: experience of the European Organization for Research and Treatment http://www.ncbi.nlm.nih.gov/pubmed/9610709. of Cancer. NCI Monogr 1988:275-278. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2451135. 502. Samlowski WE, Moon J, Kuebler JP, et al. Evaluation of the combination of docetaxel/carboplatin in patients with metastatic or 496. Minatel E, Gigante M, Franchin G, et al. Combined radiotherapy recurrent squamous cell carcinoma of the head and neck (SCCHN): a and bleomycin in patients with inoperable head and neck cancer with Southwest Oncology Group Phase II study. Cancer Invest 2007;25:182- unfavourable prognostic factors and severe symptoms. Oral Oncol 188. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17530488. 1998;34:119-122. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9682774. 503. Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced 497. Martin M, Diaz-Rubio E, Gonzalez Larriba JL, et al. Ifosfamide in head and neck cancer (E1395): an intergroup trial of the Eastern advanced epidermoid head and neck cancer. Cancer Chemother Cooperative Oncology Group. J Clin Oncol 2005;23:3562-3567. Pharmacol 1993;31:340-342. Available at: Available at: http://www.ncbi.nlm.nih.gov/pubmed/15908667. http://www.ncbi.nlm.nih.gov/pubmed/8422700. 504. Browman GP, Cronin L. Standard chemotherapy in squamous cell 498. Zhang L, Zhang Y, Huang P-Y, et al. Phase II clinical study of head and neck cancer: what we have learned from randomized trials. gemcitabine in the treatment of patients with advanced nasopharyngeal Semin Oncol 1994;21:311-319. Available at: carcinoma after the failure of platinum-based chemotherapy. Cancer http://www.ncbi.nlm.nih.gov/pubmed/7516093. Chemother Pharmacol 2008;61:33-38. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17909810. 505. Clavel M, Vermorken JB, Cognetti F, et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine 499. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in multicenter phase II study to evaluate the efficacy and toxicity of recurrent or metastatic squamous cell carcinoma of the head and neck. cetuximab as a single agent in patients with recurrent and/or metastatic A phase III study of the EORTC Head and Neck Cancer Cooperative squamous cell carcinoma of the head and neck who failed to respond to Group. Ann Oncol 1994;5:521-526. Available at: platinum-based therapy. J Clin Oncol 2007;25:2171-2177. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7522527. http://www.ncbi.nlm.nih.gov/pubmed/17538161. 506. Cohen RB. Current challenges and clinical investigations of epidermal growth factor receptor (EGFR)- and ErbB family-targeted

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

agents in the treatment of head and neck squamous cell carcinoma carcinoma. J Clin Oncol 2008;26:5518-5523. Available at: (HNSCC). Cancer Treat Rev 2014;40:567-577. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18936479. http://www.ncbi.nlm.nih.gov/pubmed/24216225. 513. Takiar V, Garden AS, Ma D, et al. Reirradiation of head and neck 507. Machiels JP, Subramanian S, Ruzsa A, et al. Zalutumumab plus cancers with intensity modulated radiation therapy: outcomes and best supportive care versus best supportive care alone in patients with analyses. Int J Radiat Oncol Biol Phys 2016;95:1117-1131. Available at: recurrent or metastatic squamous-cell carcinoma of the head and neck https://www.ncbi.nlm.nih.gov/pubmed/27354127. after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol 2011;12:333-343. Available at: 514. Eekers DB, Roelofs E, Jelen U, et al. Benefit of particle therapy in http://www.ncbi.nlm.nih.gov/pubmed/21377930. re-irradiation of head and neck patients. Results of a multicentric in silico ROCOCO trial. Radiother Oncol 2016;121:387-394. Available at: 508. Chan ATC, Hsu M-M, Goh BC, et al. Multicenter, phase II study of https://www.ncbi.nlm.nih.gov/pubmed/27639891. cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol 2005;23:3568- 515. Romesser PB, Cahlon O, Scher ED, et al. Proton beam 3576. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15809453. reirradiation for recurrent head and neck cancer: multi-institutional report on feasibility and early outcomes. Int J Radiat Oncol Biol Phys 509. Hsieh JC, Hsu CL, Ng SH, et al. Gemcitabine plus cisplatin for 2016;95:386-395. Available at: patients with recurrent or metastatic nasopharyngeal carcinoma in https://www.ncbi.nlm.nih.gov/pubmed/27084656. Taiwan: a multicenter prospective Phase II trial. Jpn J Clin Oncol 2015;45:819-827. Available at: 516. Phan J, Sio TT, Nguyen TP, et al. Reirradiation of head and neck https://www.ncbi.nlm.nih.gov/pubmed/26056323. cancers with proton therapy: outcomes and analyses. Int J Radiat Oncol Biol Phys 2016;96:30-41. Available at: 510. Chen C, Wang FH, Wang ZQ, et al. Salvage gemcitabine- https://www.ncbi.nlm.nih.gov/pubmed/27325480. vinorelbine chemotherapy in patients with metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol 517. Vargo JA, Kubicek GJ, Ferris RL, et al. Adjuvant stereotactic body 2012;48:1146-1151. Available at: radiotherapy+/-cetuximab following salvage surgery in previously http://www.ncbi.nlm.nih.gov/pubmed/22748450. irradiated head and neck cancer. Laryngoscope 2014;124:1579-1584. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24123056. 511. Zhang L, Huang Y, Hong S, et al. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic 518. Strojan P, Corry J, Eisbruch A, et al. Recurrent and second nasopharyngeal carcinoma: a multicentre, randomised, open-label, primary squamous cell carcinoma of the head and neck: when and how phase 3 trial. Lancet 2016;388:1883-1892. Available at: to reirradiate. Head Neck 2015;37:134-150. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27567279. https://www.ncbi.nlm.nih.gov/pubmed/24481720.

512. Janot F, de Raucourt D, Benhamou E, et al. Randomized trial of 519. Tanvetyanon T, Padhya T, McCaffrey J, et al. Prognostic factors postoperative reirradiation combined with chemotherapy after salvage for survival after salvage reirradiation of head and neck cancer. J Clin surgery compared with salvage surgery alone in head and neck Oncol 2009;27:1983-1991. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19289616.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

520. Lee JY, Suresh K, Nguyen R, et al. Predictors of severe long-term 527. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity toxicity after re-irradiation for head and neck cancer. Oral Oncol of pembrolizumab for treatment of recurrent or metastatic squamous 2016;60:32-40. Available at: cell carcinoma of the head and neck (KEYNOTE-012): an open-label, https://www.ncbi.nlm.nih.gov/pubmed/27531870. multicentre, phase 1b trial. Lancet Oncol 2016;17:956-965. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27247226. 521. Stoiber EM, Schwarz M, Debus J, et al. Regional cumulative maximum dose to the spinal cord in head-and-neck cancer: 528. Chow LQ, Haddad R, Gupta S, et al. Antitumor activity of considerations for re-irradiation. Radiother Oncol 2013;106:96-100. pembrolizumab in biomarker-unselected patients with recurrent and/or Available at: https://www.ncbi.nlm.nih.gov/pubmed/23260860. metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol 2016. Available 522. Nieder C, Grosu AL, Andratschke NH, Molls M. Update of human at: https://www.ncbi.nlm.nih.gov/pubmed/27646946. spinal cord reirradiation tolerance based on additional data from 38 patients. Int J Radiat Oncol Biol Phys 2006;66:1446-1449. Available at: 529. Furniss CS, McClean MD, Smith JF, et al. Human papillomavirus https://www.ncbi.nlm.nih.gov/pubmed/17084560. 16 and head and neck squamous cell carcinoma. Int J Cancer 2007;120:2386-2392. Available at: 523. Machiels JP, Haddad RI, Fayette J, et al. Afatinib versus http://www.ncbi.nlm.nih.gov/pubmed/17315185. methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing 530. Fakhry C, Gillison ML. Clinical implications of human on or after platinum-based therapy (LUX-Head & Neck 1): an open- papillomavirus in head and neck cancers. J Clin Oncol 2006;24:2606- label, randomised phase 3 trial. Lancet Oncol 2015;16:583-594. 2611. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16763272. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25892145. 531. Loughrey M, Trivett M, Lade S, et al. Diagnostic application of 524. Clement PM, Gauler T, Machiels JH, et al. Afatinib versus Epstein-Barr virus-encoded RNA in situ hybridisation. Pathology methotrexate in older patients with second-line recurrent and/or 2004;36:301-308. Available at: metastatic head and neck squamous cell carcinoma: subgroup analysis http://www.ncbi.nlm.nih.gov/pubmed/15370127. of the LUX-Head & Neck 1 trial. Ann Oncol 2016. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27084954. 532. Yap Y-Y, Hassan S, Chan M, et al. Epstein-Barr virus DNA detection in the diagnosis of nasopharyngeal carcinoma. Otolaryngol 525. Seiwert TY, Fayette J, Cupissol D, et al. A randomized, phase II Head Neck Surg 2007;136:986-991. Available at: study of afatinib versus cetuximab in metastatic or recurrent squamous http://www.ncbi.nlm.nih.gov/pubmed/17547993. cell carcinoma of the head and neck. Ann Oncol 2014;25:1813-1820. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24928832. 533. Boscolo-Rizzo P, Schroeder L, Romeo S, Pawlita M. The prevalence of human papillomavirus in squamous cell carcinoma of 526. Ferris RL, Blumenschein G, Jr., Fayette J, et al. Nivolumab for unknown primary site metastatic to neck lymph nodes: a systematic recurrent squamous-cell carcinoma of the head and neck. N Engl J Med review. Clin Exp Metastasis 2015;32:835-845. Available at: 2016. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27718784. https://www.ncbi.nlm.nih.gov/pubmed/26358913.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

534. Spiro RH. Salivary neoplasms: overview of a 35-year experience 542. Laramore GE, Krall JM, Griffin TW, et al. Neutron versus photon with 2,807 patients. Head Neck Surg 1986;8:177-184. Available at: irradiation for unresectable salivary gland tumors: final report of an http://www.ncbi.nlm.nih.gov/pubmed/3744850. RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council. Int J Radiat Oncol Biol Phys 535. Bron LP, Traynor SJ, McNeil EB, O'Brien CJ. Primary and 1993;27:235-240. Available at: metastatic cancer of the parotid: comparison of clinical behavior in 232 http://www.ncbi.nlm.nih.gov/pubmed/8407397. cases. Laryngoscope 2003;113:1070-1075. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12782825. 543. Stannard C, Vernimmen F, Carrara H, et al. Malignant salivary gland tumours: can fast neutron therapy results point the way to carbon 536. Nagliati M, Bolner A, Vanoni V, et al. Surgery and radiotherapy in ion therapy? Radiother Oncol 2013;109:262-268. Available at: the treatment of malignant parotid tumors: a retrospective multicenter http://www.ncbi.nlm.nih.gov/pubmed/24044797. study. Tumori 2009;95:442-448. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19856654. 544. Cederblad L, Johansson S, Enblad G, et al. Cancer of the parotid gland; long-term follow-up. A single centre experience on recurrence 537. Garden AS, Weber RS, Morrison WH, et al. The influence of and survival. Acta Oncol 2009;48:549-555. Available at: positive margins and nerve invasion in adenoid cystic carcinoma of the http://www.ncbi.nlm.nih.gov/pubmed/19140053. head and neck treated with surgery and radiation. Int J Radiat Oncol Biol Phys 1995;32:619-626. Available at: 545. Tanvetyanon T, Qin D, Padhya T, et al. Outcomes of postoperative http://www.ncbi.nlm.nih.gov/pubmed/7790247. concurrent chemoradiotherapy for locally advanced major salivary gland carcinoma. Arch Otolaryngol Head Neck Surg 2009;135:687-692. 538. Bell RB, Dierks EJ, Homer L, Potter BE. Management and Available at: http://www.ncbi.nlm.nih.gov/pubmed/19620591. outcome of patients with malignant salivary gland tumors. J Oral Maxillofac Surg 2005;63:917-928. Available at: 546. Ross PJ, Teoh EM, A'Hern R P, et al. Epirubicin, cisplatin and http://www.ncbi.nlm.nih.gov/pubmed/16003616. protracted venous infusion 5-Fluorouracil chemotherapy for advanced salivary adenoid cystic carcinoma. Clin Oncol (R Coll Radiol) 539. Copelli C, Bianchi B, Ferrari S, et al. Malignant tumors of intraoral 2009;21:311-314. Available at: minor salivary glands. Oral Oncol 2008;44:658-663. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19201585. http://www.ncbi.nlm.nih.gov/pubmed/17996484. 547. Debaere D, Vander Poorten V, Nuyts S, et al. Cyclophosphamide, 540. Vander Poorten V, Bradley PJ, Takes RP, et al. Diagnosis and doxorubicin, and cisplatin in advanced salivary gland cancer. B-ENT management of parotid carcinoma with a special focus on recent 2011;7:1-6. Available at: advances in molecular biology. Head Neck 2012;34:429-440. Available http://www.ncbi.nlm.nih.gov/pubmed/21563549. at: http://www.ncbi.nlm.nih.gov/pubmed/21618326. 548. Vermorken JB, Verweij J, de Mulder PH, et al. Epirubicin in 541. Griffin BR, Laramore GE, Russell KJ, et al. Fast neutron patients with advanced or recurrent adenoid cystic carcinoma of the radiotherapy for advanced malignant salivary gland tumors. Radiother head and neck: a phase II study of the EORTC Head and Neck Cancer Oncol 1988;12:105-111. Available at: Cooperative Group. Ann Oncol 1993;4:785-788. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3406455. http://www.ncbi.nlm.nih.gov/pubmed/8280659.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

549. Licitra L, Cavina R, Grandi C, et al. Cisplatin, doxorubicin and 557. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base cyclophosphamide in advanced salivary gland carcinoma. A phase II report on cutaneous and noncutaneous melanoma: a summary of trial of 22 patients. Ann Oncol 1996;7:640-642. Available at: 84,836 cases from the past decade. The American College of Surgeons http://www.ncbi.nlm.nih.gov/pubmed/8879381. Commission on Cancer and the American Cancer Society. Cancer 1998;83:1664-1678. Available at: 550. Laurie SA, Ho AL, Fury MG, et al. Systemic therapy in the http://www.ncbi.nlm.nih.gov/pubmed/9781962. management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. Lancet Oncol 2011;12:815- 558. Bachar G, Loh KS, O'Sullivan B, et al. Mucosal melanomas of the 824. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21147032. head and neck: experience of the Princess Margaret Hospital. Head Neck 2008;30:1325-1331. Available at: 551. Laurie SA, Licitra L. Systemic therapy in the palliative management http://www.ncbi.nlm.nih.gov/pubmed/18704964. of advanced salivary gland cancers. J Clin Oncol 2006;24:2673-2678. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16763282. 559. McLean N, Tighiouart M, Muller S. Primary mucosal melanoma of the head and neck. Comparison of clinical presentation and 552. Gilbert J, Li Y, Pinto HA, et al. Phase II trial of taxol in salivary histopathologic features of oral and sinonasal melanoma. Oral Oncol gland malignancies (E1394): a trial of the Eastern Cooperative 2008;44:1039-1046. Available at: Oncology Group. Head Neck 2006;28:197-204. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18396446. http://www.ncbi.nlm.nih.gov/pubmed/16470745. 560. Patel SG, Prasad ML, Escrig M, et al. Primary mucosal malignant 553. Airoldi M, Pedani F, Succo G, et al. Phase II randomized trial melanoma of the head and neck. Head Neck 2002;24:247-257. comparing vinorelbine versus vinorelbine plus cisplatin in patients with Available at: http://www.ncbi.nlm.nih.gov/pubmed/11891956. recurrent salivary gland malignancies. Cancer 2001;91:541-547. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11169936. 561. Meleti M, Leemans CR, de Bree R, et al. Head and neck mucosal melanoma: experience with 42 patients, with emphasis on the role of 554. Chau NG, Hotte SJ, Chen EX, et al. A phase II study of sunitinib in postoperative radiotherapy. Head Neck 2008;30:1543-1551. Available recurrent and/or metastatic adenoid cystic carcinoma (ACC) of the at: http://www.ncbi.nlm.nih.gov/pubmed/18704960. salivary glands: current progress and challenges in evaluating molecularly targeted agents in ACC. Ann Oncol 2012;23:1562-1570. 562. Douglas CM, Malik T, Swindell R, et al. Mucosal melanoma of the Available at: http://www.ncbi.nlm.nih.gov/pubmed/22080184. head and neck: radiotherapy or surgery? J Otolaryngol Head Neck Surg 2010;39:385-392. Available at: 555. Marcus DM, Marcus RP, Prabhu RS, et al. Rising incidence of http://www.ncbi.nlm.nih.gov/pubmed/20643003. mucosal melanoma of the head and neck in the United States. J Skin Cancer 2012;2012:231693. Available at: 563. Gavriel H, McArthur G, Sizeland A, Henderson M. Review: http://www.ncbi.nlm.nih.gov/pubmed/23251803. mucosal melanoma of the head and neck. Melanoma Res 2011;21:257- 266. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21540752. 556. McLaughlin CC, Wu XC, Jemal A, et al. Incidence of noncutaneous melanomas in the U.S. Cancer 2005;103:1000-1007. Available at: 564. Temam S, Mamelle G, Marandas P, et al. Postoperative http://www.ncbi.nlm.nih.gov/pubmed/15651058. radiotherapy for primary mucosal melanoma of the head and neck.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

Cancer 2005;103:313-319. Available at: Otolaryngol Head Neck Surg 2010;136:1219-1225. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15578718. http://www.ncbi.nlm.nih.gov/pubmed/21173371.

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566. Ang KK, Peters LJ, Weber RS, et al. Postoperative radiotherapy 573. Owens JM, Roberts DB, Myers JN. The role of postoperative for cutaneous melanoma of the head and neck region. Int J Radiat adjuvant radiation therapy in the treatment of mucosal melanomas of Oncol Biol Phys 1994;30:795-798. Available at: the head and neck region. Arch Otolaryngol Head Neck Surg http://www.ncbi.nlm.nih.gov/pubmed/7960981. 2003;129:864-868. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12925346. 567. Agrawal S, Kane JM, 3rd, Guadagnolo BA, et al. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for 574. Gilligan D, Slevin NJ. Radical radiotherapy for 28 cases of mucosal clinically advanced, high-risk, lymph node-metastatic melanoma. melanoma in the nasal cavity and sinuses. Br J Radiol 1991;64:1147- Cancer 2009;115:5836-5844. Available at: 1150. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1773274. http://www.ncbi.nlm.nih.gov/pubmed/19701906. 575. Shibuya H, Takeda M, Matsumoto S, et al. The efficacy of radiation 568. Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant therapy for a malignant melanoma in the mucosa of the upper jaw: an radiotherapy versus observation alone for patients at risk of lymph-node analytic study. Int J Radiat Oncol Biol Phys 1993;25:35-39. Available at: field relapse after therapeutic lymphadenectomy for melanoma: a http://www.ncbi.nlm.nih.gov/pubmed/8416880. randomised trial. Lancet Oncol 2012;13:589-597. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22575589. 576. Wada H, Nemoto K, Ogawa Y, et al. A multi-institutional retrospective analysis of external radiotherapy for mucosal melanoma of 569. Moore ES, Martin H. Melanoma of the upper respiratory tract and the head and neck in Northern Japan. Int J Radiat Oncol Biol Phys oral cavity. Cancer 1955;8:1167-1176. Available at: 2004;59:495-500. Available at: http://www.ncbi.nlm.nih.gov/pubmed/13270234. http://www.ncbi.nlm.nih.gov/pubmed/15145168.

570. Moreno MA, Roberts DB, Kupferman ME, et al. Mucosal 577. Bonnen MD, Ballo MT, Myers JN, et al. Elective radiotherapy melanoma of the nose and paranasal sinuses, a contemporary provides regional control for patients with cutaneous melanoma of the experience from the M. D. Anderson Cancer Center. Cancer head and neck. Cancer 2004;100:383-389. Available at: 2010;116:2215-2223. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14716775. http://www.ncbi.nlm.nih.gov/pubmed/20198705. 578. Ballo MT, Bonnen MD, Garden AS, et al. Adjuvant irradiation for 571. Benlyazid A, Thariat J, Temam S, et al. Postoperative radiotherapy cervical lymph node metastases from melanoma. Cancer in head and neck mucosal melanoma: a GETTEC study. Arch 2003;97:1789-1796. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12655537.

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NCCN Guidelines Version 1.2018 NCCN Guidelines Index Table of Contents Head and Neck Cancers Discussion

579. Wu AJ, Gomez J, Zhung JE, et al. Radiotherapy after surgical 586. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a resection for head and neck mucosal melanoma. Am J Clin Oncol therapeutic target in metastatic melanoma. JAMA 2011;305:2327-2334. 2010;33:281-285. Available at: Available at: http://www.ncbi.nlm.nih.gov/pubmed/21642685. http://www.ncbi.nlm.nih.gov/pubmed/19823070. 587. Torres-Cabala CA, Wang WL, Trent J, et al. Correlation between 580. Anker CJ, Grossmann KF, Atkins MB, et al. Avoiding severe KIT expression and KIT mutation in melanoma: a study of 173 cases toxicity from combined BRAF inhibitor and radiation treatment: with emphasis on the acral-lentiginous/mucosal type. Mod Pathol consensus guidelines from the Eastern Cooperative Oncology Group 2009;22:1446-1456. Available at: (ECOG). Int J Radiat Oncol Biol Phys 2016;95:632-646. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19718013. https://www.ncbi.nlm.nih.gov/pubmed/27131079. 588. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of 581. Seetharamu N, Ott PA, Pavlick AC. Mucosal melanomas: a case- KIT in distinct subtypes of melanoma. J Clin Oncol 2006;24:4340-4346. based review of the literature. Oncologist 2010;15:772-781. Available Available at: http://www.ncbi.nlm.nih.gov/pubmed/16908931. at: http://www.ncbi.nlm.nih.gov/pubmed/20571149. 589. Turri-Zanoni M, Medicina D, Lombardi D, et al. Sinonasal mucosal 582. Narasimhan K, Kucuk O, Lin HS, et al. Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series melanoma: a 13-year experience at a single institution. Skull Base of 32 cases. Head Neck 2013;35:1066-1077. Available at: 2009;19:255-262. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22791410. http://www.ncbi.nlm.nih.gov/pubmed/20046593.

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